Use of pyrroloquinoline compounds to kill clinically latent microorganisms

ABSTRACT

There is provided the use of compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and X have meanings given in the description, for the preparation of a medicament for killing clinically latent microorganisms. There is also provided the use of compounds of formula I for treating microbial infections, as well as certain compounds of formula I per se.

This invention relates to the use of compounds based upon thepyrrolo[3,2-c]quinoline ring system to kill clinically latentmicroorganisms. The invention further relates to the use of suchcompounds to treat microbial infections, as well as, inter alia, certainof the compounds per se.

The listing or discussion of a prior-published document in thisspecification should not necessarily be taken as an acknowledgement thatthe document is part of the state of the art or is common generalknowledge.

Before the introduction of antibiotics, patients suffering from acutebacterial infections (e.g. tuberculosis or pneumonia) had a low chanceof survival. For example, mortality from tuberculosis was around 50%.

Although the introduction of antibacterial agents in the 1940s and 1950srapidly changed this picture, bacteria have responded by progressivelygaining resistance to commonly used antibiotics. Now, every country inthe world has antibiotic-resistant bacteria. Indeed, more than 70% ofbacteria that give rise to hospital acquired infections in the USAresist at least one of the main antimicrobial agents that are typicallyused to fight infection (see Nature Reviews, Drug Discovery 1, 895-910(2002)).

One way of tackling the growing problem of resistant bacteria is thedevelopment of new classes of antimicrobial agents. However, until theintroduction of linezolid in 2000, there had been no new class ofantibiotic marketed for over 37 years. Moreover, even the development ofnew classes of antibiotic provides only a temporary solution, and indeedthere are already reports of resistance of certain bacteria to linezolid(see Lancet 357, 1179 (2001) and Lancet 358, 207-208 (2001)).

In order to develop more long-term solutions to the problem of bacterialresistance, it is clear that alternative approaches are required. Onesuch alternative approach is to minimise, as much as is possible, theopportunities that bacteria are given for developing resistance toimportant antibiotics.

Thus, strategies that can be adopted include limiting the use ofantibiotics for the treatment of non-acute infections, as well ascontrolling which antibiotics are fed to animals in order to promotegrowth.

However, in order to tackle the problem more effectively, it isnecessary to gain an understanding of the actual mechanisms by whichbacteria generate resistance to antibiotic agents. To do this requiresfirst a consideration of how current antibiotic agents work to killbacteria.

Antimicrobial agents target essential components of bacterialmetabolism. For example, the β-lactams (e.g. penicillins andcephalosporins) inhibit cell wall synthesis, whereas other agentsinhibit a diverse range of targets, such as DNA gyrase (quinolones) andprotein synthesis (e.g. macrolides, aminoglycosides, tetracyclines andoxazolidinones). The range of organisms against which the antimicrobialagents are effective varies, depending upon which organisms are heavilyreliant upon the metabolic step(s) that is/are inhibited. Further, theeffect upon bacteria can vary from a mere inhibition of growth (i.e. abacteriostatic effect, as seen with agents such as the tetracyclines) tofull killing (i.e. a bactericidal effect, as seen, for example, withpenicillin).

Bacteria have been growing on Earth for more than 3 billion years and,in that time, have needed to respond to vast numbers of environmentalstresses. It is therefore perhaps not surprising that bacteria havedeveloped a seemingly inexhaustible variety of mechanisms by which theycan respond to the metabolic stresses imposed upon them by antibioticagents. Indeed, mechanisms by which the bacteria can generate resistanceinclude strategies as diverse as inactivation of the drug, modificationof the site of action, modification of the permeability of the cellwall, overproduction of the target enzyme and bypass of the inhibitedsteps.

Nevertheless, the rate of resistance emerges to a particular agent hasbeen observed to vary widely, depending upon factors such as the agent'smechanism of action, whether the agent's mode of killing is time- orconcentration-dependent, the potency against the population of bacteriaand the magnitude and duration of the available serum concentration.

It has been proposed (see Science 264, 388-393 (1994)) that agents thattarget single enzymes (e.g. rifampicin) are the most prone to thedevelopment of resistance. Further, the longer that suboptimal levels ofantimicrobial agent are in contact with the bacteria, the more likelythe emergence of resistance.

Moreover, it is now known that many bacterial infections includesub-populations of bacteria that are phenotypically resistant toantimicrobials (see, for example: J. Antimicrob. Chemother. 4, 395-404(1988); J. Med. Microbiol. 38, 197-202 (1993); J. Bacteriol. 182,1794-1801 (2000); ibid. 182, 6358-6365 (2000); ibid. 183, 6746-6751(2001); FEMS Microbiol. Lett. 202, 59-65 (2001); and Trends inMicrobiology 13, 34-40 (2005)). There appear to be several types of suchphenotypically resistant bacteria, including persisters,stationary-phase bacteria, as well as those in the depths of biofilms.However, each of these types is characterised by its low rate of growth(compared to log-phase bacteria under the same conditions). Nutritionalstarvation and high cell densities are also common characteristics ofsuch bacteria.

Although resistant to antimicrobial agents in their slow-growing state,phenotypically resistant bacteria differ from those that aregenotypically resistant in that they regain their susceptibility toantimicrobials when they return to a fast-growing state (e.g. whennutrients become more readily available to them).

The presence of phenotypically resistant bacteria in an infection leadsto the need for prolonged courses of antimicrobial agents, comprisingmultiple doses. This is because the resistant, slowly multiplyingbacteria provide a pool of “latent” organisms that can convert to afast-growing state when the conditions allow (thereby effectivelyre-initiating the infection). Multiple doses over time deal with thisissue by gradually killing off the “latent” bacteria that convert to“active” form.

However, dealing with “latent” bacteria by administering prolongedcourses of antimicrobials poses its own problems. That is, prolongedexposure of bacteria to suboptimal concentrations of antimicrobial agentcan lead to the emergence of genotypically resistant bacteria, which canthen multiply rapidly in the presence of even high concentrations of theantimicrobial.

Long courses of antimicrobials are more likely to encourage theemergence of genotypic resistance than shorter courses on the groundsthat non-multiplying bacterial will tend to survive and, interestingly,probably have an enhanced ability to mutate to resistance (see, forexample: Proc. Natl. Acad. Sci. USA 92, 11736-11740 (1995); J.Bacteriol. 179, 6688-6691 (1997); and Antimicrob. Agents Chemother. 44,1771-1777 (2000)). For example, non-dividing E. coli continually mutatesto ciprofloxacin resistance during a seven-day exposure to the agent.[129] Thus, “latent” bacteria might be one of the sources ofgenotypically resistant bacteria.

In the light of the above, a new approach to combating the problem ofbacterial resistance might be to select and develop antimicrobial agentson the basis of their ability to kill “latent” microorganisms. Theproduction of such agents would allow, amongst other things, for theshortening of chemotherapy regimes in the treatment of microbialinfections, thus reducing the frequency with which genotypicalresistance arises in microorganisms.

Certain pyrrolo[2,3-c]quinolines, as well as their 2,3-dihydroderivatives, are disclosed in: Science of Synthesis 15, 389-549 (2005);Heterocycles 48(2), 221-226 (1998); Tetrahedron 52(2), 647-60 (1996);ibid. 51(47), 12869-82 (1995); Synlett (Spec. Issue), 507-509 (1995);Tetrahedron Lett. 34(22), 3629-32 (1993); JP 48030280; JP 48030078; JP48030077; Chem. & Pharm. Bull. 20(1), 109-16 (1972); Yakugaku Zasshi 77,85-9 (1957); ibid. 81, 363-9 (1961); ibid. 81, 479-83 and 484-9 (1961);Acta Crystallographica C43(11), 2206-9 (1987); Acta Chimica Sinica41(7), 668-71 (1984); ibid. 42(5), 470-8 (1984); J. Chem. Soc., PerkinTrans. 1 1457-63 (1997); and Anti-Cancer Drug Design 9, 51-67 (1994).

Medical utilities of such compounds, for examples as inhibitors of thegastric (H⁺/K⁺)-ATPase, as agents for the treatment of diseases relatedto corticotropin-releasing factor (CRF) and/or corticotropin-releasingfactor receptor, as agents for the prevention and/or treatment ofneurodegenerative diseases, as inhibitors of the effects of freeradicals, as immunoregulators, as antiinflammatory agents, asanalgesics, as antipyretic agents, as hypotensive agents, as inhibitorsof enzymes of the kynurenine pathway, as cytotoxic agents, or asinhibitors of HIV particle formation are mentioned in WO 97/44342; WO98/05660; WO 99/09029; WO 00/01696; WO 01/42247; WO 2005/076861; EP 0307 078; EP 0 587 473; JP 06092963; U.S. Pat. No. 4,771,052; U.S. Pat.No. 6,995,163; J. Med. Chem. 33(2), 527-33 (1990); Drug Design andDelivery 7, 131-8 (1991); J. Med. Chem. 35, 1845-52 (1992); Farmaco54(3), 152-160 (1999); Bioorg. Med. Chem. Lett. 9, 2819-22 (1999);Biochem. Biophys. Acta 1029, 24-32 (1990); and Eur. J. Med. Chem. 32,815-22 (1997).

Activity against malaria parasites, Trypanosoma cruzi and amoeba forcertain 2,3-dihydropyrrolo[3,2-c]quinoline compounds is mentioned in GB725 745, U.S. Pat. No. 2,691,023, U.S. Pat. No. 2,691,024 and Synthesis903-906 (2005).

Further, activity against certain growing bacteria for a small number of2,3-dihydropyrrolo[3,2-c]quinoline compounds is mentioned in YakugakuZasshi 77, 90-3 (1957).

We have now found, surprisingly, that pyrrolo[2,3-c]quinolines, or their2,3-dihydro derivatives, may be used to kill clinically latentmicroorganisms.

According to a first aspect of the invention, there is provided the useof a compound of formula I, or a pharmaceutically-acceptable derivativethereof, for the preparation of a medicament for killing clinicallylatent microorganisms, wherein the compound of formula I is representedby the structure

wherein

R¹ represents

-   (a) H;-   (b) C₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl (which latter    three groups are optionally substituted by one or more substituents    selected from halo, nitro, CN, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆    alkynyl, C₃₋₈ cycloalkyl (which latter three groups are optionally    substituted by one or more substituents selected from OH, ═O, halo,    C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(4a), S(O)₁R^(4b),    S(O)₂N(R^(4c))(R^(4d)), N(R^(4e))S(O)₂R^(4f), N(R^(4g))(R⁴),    B¹—C(O)—B²—R^(4i), aryl and Het¹, and which C₃₋₁₂ cycloalkyl or    C₄₋₁₂ cycloalkenyl groups may additionally be substituted by ═O),-   (c) aryl or-   (d) Het²;

R² represents

-   (a) H;-   (b) C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl or    C₄₋₁₂ cycloalkenyl, which latter five groups are optionally    substituted by one or more substituents selected from halo, nitro,    CN, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₃₋₈ cycloalkyl (which    latter three groups are optionally substituted by one or more    substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy), OR^(5a), S(O)_(p)R^(5b), S(O)₂N(R^(5e))(R⁵),    N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)), B³—C(O)—B⁴—R^(5i), aryl and    Het³, and which C₃₋₁₂ cycloalkyl or C₄₋₁₂ cycloalkenyl groups may    additionally be substituted by ═O,-   (c) aryl or-   (d) Het⁴;

R³ represents H or one to four substituents on the fused benzene ringselected from

-   (a) halo,-   (b) CN,-   (c) C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl or    C₄₋₁₂ cycloalkenyl, which latter five groups are optionally    substituted by one or more substituents selected from halo, nitro,    CN, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₃₋₈ cycloalkyl (which    latter three groups are optionally substituted by one or more    substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy), OR^(6a), S(O)_(q)R^(6b), S(O)₂N(R^(6e))(R^(6d)),    N(R^(6e))S(O)₂R^(6f), N(R^(6g))(R^(6h)), B⁵—C(O)—B⁶—R^(6i), aryl and    Het⁵, and which C₃₋₁₂ cycloalkyl or C₄₋₁₂ cycloalkenyl groups may    additionally be substituted by ═O,-   (d) OR^(7a),-   (e) S(O)_(r)R^(7b),-   (f) S(O)₂N(R^(7e))(R^(7d)),-   (g) N(R^(7e))S(O)₂R^(7f),-   (h) N(R^(7g))(R^(7h)),-   (i) B⁷—C(O)—B⁸—R^(7i),-   (j) aryl or-   (k) Het⁶;

R^(4a) to R^(4i), R^(5a) to R^(5i), R^(6a) to R^(6i) and R^(7a) toR^(7i) independently represent, at each occurrence,

-   (a) H,-   (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl (which latter three    groups are optionally substituted by one or more substituents    selected from halo, OH, C₁₋₆ alkoxy, aryl and Het⁷),

(c) C₃₋₁₀ cycloalkyl, C₄₋₁₀ cycloalkenyl (which latter two groups areoptionally substituted by one or more substituents selected from halo,OH, ═O, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl and Het⁸),

-   (d) aryl or-   (e) Het⁹,    provided that R^(4b), R^(5b), R^(6b) or R^(7b) does not represent H    when n, p, q or r, respectively is 1 or 2;-   X represents-   —C(R^(8a))(R^(8b))—C(R^(8c))(R^(8d))— or-   (b) —C(R^(8e))═C(R^(8f))—;    R^(8a) to R^(8f) independently represent H, halo or C₁₋₄ alkyl;    each aryl independently represents a C₆₋₁₀ carbocyclic aromatic    group, which group may comprise either one or two rings and may be    substituted by one or more substituents selected from-   (a) halo,-   (b) CN,-   (c) C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl or    C₄₋₁₂ cycloalkenyl, which latter five groups are optionally    substituted by one or more substituents selected from halo, nitro,    CN, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₃₋₈ cycloalkyl (which    latter three groups are optionally substituted by one or more    substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy), OR^(9a), S(O)_(t)R^(9b), S(O)₂N(R^(9c))(R^(9d)),    N(R^(9e))S(O)₂R^(9f), N(R^(9g))(R^(9h)), B⁹—C(O)—B¹⁰—R^(9i), phenyl,    naphthyl (which latter two groups are optionally substituted by one    or more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy) and Het¹⁰, and which C₃₋₁₂ cycloalkyl or C₄₋₁₂ cycloalkenyl    groups may additionally be substituted by ═O,-   (d) OR^(10a),-   (e) S(O)_(u)R^(10b),-   (f) S(O)₂N(R^(10c))(R^(10d)),-   (g) N(R^(10e))S(O)₂R^(10f),-   (h) N(R^(10g))(R^(10h)),-   (i) B¹¹—C(O)—B¹²R^(10i),-   (j) phenyl (which latter group is optionally substituted by one or    more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy) or-   (k) Het¹¹;

R^(9a) to R^(9i) and R^(10a) to R^(10i) independently represent, at eachoccurrence,

-   (a) H,-   (b) C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl,    C₄₋₁₂ cycloalkenyl (which latter five groups are optionally    substituted by one or more substituents selected from halo, OH, C₁₋₆    alkyl, C₃₋₁₂ cycloalkyl, C₄₋₁₂ cycloalkenyl (which latter two groups    are optionally substituted by one or more substituents selected from    OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), C₁₋₆ alkoxy, NH₂,    N(H)—C₁₋₆ alkyl, N(C₁₋₆ alkyl)₂, phenyl (which latter group is    optionally substituted by one or more substituents selected from OH,    halo, C₁₋₄ alkyl and C₁₋₄ alkoxy) and Het¹², and which C₃₋₁₂    cycloalkyl or C₄₋₁₂ cycloalkenyl groups may additionally be    substituted by ═O,-   (c) phenyl (which latter group is optionally substituted by one or    more substituents selected from OH, CN, halo, C₁₋₆ alkyl and C₁₋₆    alkoxy) or-   (e) Het¹³,    provided that R^(9b) or R^(10b) does not represent H when t or u,    respectively is 1 or 2;

Het¹ to Het¹³ independently represent 4- to 14-membered heterocyclicgroups containing one or more heteroatoms selected from oxygen, nitrogenand/or sulfur, which heterocyclic groups may comprise one, two or threerings and may be substituted by one or more substituents selected from

-   (a) halo,-   (b) CN,-   (c) C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl or    C₄₋₁₂ cycloalkenyl, which latter five groups are optionally    substituted by one or more substituents selected from halo, nitro,    CN, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₃₋₈ cycloalkyl (which    latter three groups are optionally substituted by one or more    substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy), OR^(11a), S(O)_(v)R^(11b), S(O)₂N(R^(11c))(R^(11d)),    N(R^(11e))S(O)₂R^(11f), N(R^(11g))(R^(11h)), B¹³—C(O)—B¹⁴—R^(11i),    phenyl, naphthyl (which latter two groups are optionally substituted    by one or more substituents selected from OH, halo, C₁₋₄ alkyl and    C₁₋₄ alkoxy) and Het^(a), and which C₃₋₁₂ cycloalkyl or C₄₋₁₂    cycloalkenyl groups may additionally be substituted by ═O,-   (d) OR^(12a),-   (e) ═O,-   (f) S(O)_(w)R^(12b),-   (g) S(O)₂N(R^(12e))(R^(12d)),-   (h) N(R^(12e))S(O)₂R^(12f),-   (i) N(R^(12g))(R^(12h)),-   (j) B¹⁵—C(O)—B¹⁶—R^(12i),-   (k) phenyl (which latter group is optionally substituted by one or    more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy) or-   (l) Het^(b);

R^(11a) to R^(11i) and R^(12a) to R^(12i) independently represent, ateach occurrence,

-   (a) H,-   (b) C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl,    C₄₋₁₂ cycloalkenyl (which latter five groups are optionally    substituted by one or more substituents selected from halo, OH, C₁₋₆    alkyl, C₃₋₁₂ cycloalkyl, C₄₋₁₂ cycloalkenyl (which latter two groups    are optionally substituted by one or more substituents selected from    OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), C₁₋₆ alkoxy, phenyl    (which latter group is optionally substituted by one or more    substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy) and    Het^(c), and which C₃₋₁₂ cycloalkyl or C₄₋₁₂ cycloalkenyl groups may    additionally be substituted by ═O,-   (c) phenyl (which latter group is optionally substituted by one or    more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy) or-   (e) Het^(d),    provided that R^(11b) or R^(12b)) does not represent H when v or w,    respectively is 1 or 2;

B¹ to B¹⁶ independently represent a direct bond, O, S, NH or N(R¹³); n,p, q, r, s, t, u, v and w independently represent 0, 1 or 2;

R¹³ represents

-   (a) C₁₋₆ alkyl,-   (b) phenyl (which latter group is optionally substituted by one or    more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy),-   (c) C₃₋₇ cycloalkyl (which latter group is are optionally    substituted by one or more substituents selected from OH, ═O, halo,    C₁₋₄ alkyl and C₁₋₄ alkoxy) or

(e) Het^(c);

Het^(a) to Het^(e) independently represent 5- or 6-membered heterocyclicgroups containing one to four heteroatoms selected from oxygen, nitrogenand/or sulfur, which heterocyclic groups may be substituted by one ormore substituents selected from halo, ═O and C₁₋₆ alkyl; and

unless otherwise specified

-   (i) alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, as    well as the alkyl part of alkoxy groups, may be substituted by one    or more halo atoms, and-   (ii) cycloalkyl and cycloalkenyl groups may comprise one or two    rings and may additionally be ring-fused to one or two benzene    rings.

When used herein, the term “pharmaceutically-acceptable derivative”includes references to:

-   (a) pharmaceutically-acceptable salts with either acids or bases    (e.g. acid addition salts); and/or-   (b) solvates (e.g. hydrates)

Acid addition salts that may be mentioned include carboxylate salts(e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate,heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate,propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate,α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate,phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts),halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts(e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate,xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1- or 2-naphthalene-sulfonate or1,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, andthe like.

The term “pharmaceutically-acceptable derivative” also includesreferences to:

-   (a) C₁₋₄ alkyl quaternary ammonium salts; or-   (b) N-oxides,    at either of the two tertiary N-atoms of the    (2,3-dihydro-)pyrroloquinoline ring system or at a tertiary N-atom    that may be present in any of substituents R¹, R² and R³.

For the avoidance of doubt, the definitions of the terms aryl, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkoxy groups providedabove apply, unless otherwise stated, at each usage of such termsherein. Further, the one or two benzene rings that may be fused tocycloalkyl groups may bear one or more of the substituents defined inrespect of the relevant cycloalkyl group.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

Heterocyclic (Het¹ to Het¹³ and Het^(a) to Het^(e)) groups may be fullysaturated, partly unsaturated, wholly aromatic or partly aromatic incharacter. Values of heterocyclic (Het¹ to Het¹³ and Het^(a) to Het^(e))groups that may be mentioned include 1-azabicyclo[2.2.2]octanyl,benzimidazolyl, benzo[c]isoxazolidinyl, benzisoxazolyl, benzodioxanyl,benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl,benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazolidinyl, benzoxazolyl,benzopyrazolyl, benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl,benzothiazolyl, benzothienyl, benzotriazolyl, chromanyl, chromenyl,cinnolinyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furanyl,1,3-dihydrobenzo-[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, furanyl,hexahydropyrimidinyl, hydantoinyl, imidazolyl, imidazo[1,2-a]pyridinyl,imidazo[2,3-b]thiazolyl, indolyl, isoquinolinyl, isoxazolidinyl,isoxazolyl, maleimido, morpholinyl, naphtho[1,2-b]furanyl, oxadiazolyl,1,2- or 1,3-oxazinanyl, oxazolyl, phthalazinyl, piperazinyl,piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl,pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,pyrrolo[2,3-c]pyridinyl, pyrrolyl, quinazolinyl, quinolinyl, sulfolanyl,3-sulfolenyl, 4,5,6,7-tetrahydrobenzimidazolyl,4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydro-benzo[e]pyrimidine,tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydro-pyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thieno[5,1-c]pyridinyl,thiochromanyl, triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl, xanthenyland the like. Values of Het¹ that may be mentioned include benzodioxanyl(e.g. benzodioxan-2-yl), benzodioxolyl (e.g. benzodioxol-5-yl),pyrazinyl (e.g. pyrazin-2-yl), pyridinyl (e.g. pyridin-2-yl orpyridin-3-yl), pyrrolidinonyl (e.g. pyrrolidinon-1-yl) andtetrahydrofuranyl (e.g. tetrahydrofuran-2-yl).

Values of Het² that may be mentioned include benzimidazolyl (e.g.benzimidazol-2-yl), piperidinyl (e.g. piperidin-4-yl), pyridinyl (e.g.pyridin-3-yl) and pyrrolidinyl (e.g. pyrrolidin-3-yl).

Values of Het⁶ that may be mentioned include morpholinyl (e.g.morpholin-4-yl) and piperidinyl (e.g. piperidin-4-yl).

Values of Het⁹ that may be mentioned include piperidinyl (e.g.piperidin-1-yl).

Values of Het¹¹ that may be mentioned include piperazinyl (e.g.piperazin-1-yl), piperidinyl (e.g. piperidin-1-yl) and pyridinyl (e.g.pyridin-3-yl).

Values of Het¹³ that may be mentioned include pyridinyl (e.g.pyridin-3-yl).

Compounds of formula I that may be mentioned include:

-   (a) those in which R¹ and/or R² represents H; and-   (b) those in which R¹ represents other than H and/or R² represents    other than H.

When used herein, the term “microorganisms” means:

-   (a) fungi (as defined below); and, particularly-   (b) bacteria (as defined below).

References herein to the terms “microbial”, “antimicrobial” and“antimicrobially” shall be interpreted in accordance with the definitionof “microorganisms”. For example, the term “microbial” means fungal or,particularly, bacterial.

When used herein, the term “clinically latent” includes references tomicroorganisms that are viable but non-culturable (e.g. bacteria thatcannot be detected by standard culture techniques but that aredetectable and quantifiable by techniques such as broth dilutioncounting, microscopy, or molecular techniques such as polymerase chainreaction).

The term “clinically latent” also includes references to microorganismsthat are phenotypically tolerant, for example microorganisms that:

-   (a) are sensitive (e.g. in log phase) to the biostatic (e.g.    bacteriostatic) effects of conventional antimicrobial agents (i.e.    microorganisms for which the minimum inhibitory concentration (MIC)    of a conventional antimicrobial is substantially unchanged); but-   (b) possess drastically decreased susceptibility to drug-induced    killing (e.g. microorganisms for which, with any given conventional    antimicrobial agent, the ratio of minimum microbicidal concentration    (e.g. minimum bactericidal concentration, MBC) to MIC is 10 or    more).

In relation to point (a) above, “substantially unchanged” refers to MICvalues that are anywhere from 50 to 200% (e.g. 90 to 110%) of the valuedetermined under standard conditions for the microorganism andconventional antimicrobial agent concerned.

For the avoidance of doubt, the term “clinically latent” excludesreferences to microorganisms that are genotypically resistant toconventional antimicrobial agents (i.e. microorganisms that differgenetically from antimicrobial-sensitive members of the same genus andthat display an increased MIC (e.g. in log phase) for one or moreconventional antimicrobial agents compared to saidantimicrobial-sensitive microorganisms).

The term “clinically latent” further includes references tomicroorganisms that:

-   (i) are metabolically active; but-   (ii) have a growth rate that is below the threshold of infectious    disease expression.

The term “threshold of infectious disease expression” will be understoodby those skilled in the art to include references to the growth ratethreshold below which the symptoms of infectious disease (in a patientinfected with the relevant microorganism) are absent.

In relation to point (i) above, metabolic activity of latentmicroorganisms can be determined by several methods known to thoseskilled in the art, for example by measuring mRNA levels in themicroorganisms or by determining their rate of uridine uptake. In thisrespect, the term “clinically latent” further includes references tomicroorganisms that, compared to the same number of microorganisms underlogarithmic growth conditions (in vitro or in vivo), possess reduced butstill significant levels of:

-   (I) mRNA (e.g. from 0.0001 to 50%, such as from 1 to 30, 5 to 25 or    10 to 20%, of the level of mRNA); and/or-   (II) uridine (e.g. [³H]uridine) uptake (e.g. from 0.0005 to 50%,    such as from 1 to 40, 15 to 35 or 20 to 30% of the level of    [³H]uridine uptake).

When used herein, the term “conventional antimicrobial agent(s)” means:

-   (a) conventional antifungal agents; and, particularly-   (b) conventional antibacterial agents,    wherein each of (a) and (b) is as defined below.

When used herein, the term “conventional antibacterial agent(s)” includereferences to bactericidal and bacteristatic agents that are known inthe prior art (i.e. agents that have been selected and developed on thebasis of their MICs—namely their ability to inhibit the growth ofbacteria). In this respect, particular conventional antibiotic agentsthat may be mentioned include any one or more of the following.

-   (a) β-Lactams, including:    -   (i) penicillins, such as        -   (I) benzylpenicillin, procaine benzylpenicillin,            phenoxy-methylpenicillin, methicillin, propicillin,            epicillin, cyclacillin, hetacillin, 6-aminopenicillanic            acid, penicillic acid, penicillanic acid sulphone            (sulbactam), penicillin G, penicillin V, phenethicillin,            phenoxymethylpenicillinic acid, azlocillin, carbenicillin,            cloxacillin, D-(−)-penicillamine, dicloxacillin, nafcillin            and oxacillin,        -   (II) penicillinase-resistant penicillins (e.g.            flucloxacillin),        -   (III) broad-spectrum penicillins (e.g. ampicillin,            amoxicillin, metampicillin and bacampicillin),        -   (IV) antipseudomonal penicillins (e.g. carboxypenicillins            such as ticarcillin or ureidopenicillins such as            piperacillin),        -   (V) mecillinams (e.g. pivmecillinam), or        -   (VI) combinations of any two or more of the agents mentioned            at (I) to (V) above, or combinations of any of the agents            mentioned at (I) to (V) above with a β-lactamase inhibitor            such as tazobactam or, particularly, clavulanic acid (which            acid is optionally in metal salt form, e.g. in salt form            with an alkali metal such as sodium or, particularly,            potassium);    -   (ii) cephalosporins, such as cefaclor, cefadroxil, cefalexin        (cephalexin), cefcapene, cefcapene pivoxil, cefdinir,        cefditoren, cefditoren pivoxil, cefixime, cefotaxime, cefpirome,        cefpodoxime, cefpodoxime proxetil, cefprozil, cefradine,        ceftazidime, cefteram, cefteram pivoxil, ceftriaxone,        cefuroxime, cefuroxime axetil, cephaloridine, cephacetrile,        cephamandole, cephaloglycine, ceftobiprole, PPI-0903 (TAK-599),        7-aminocephalosporanic acid, 7-aminodes-acetoxycephalosporanic        acid, cefamandole, cefazolin, cefmetazole, cefoperazone,        cefsulodin, cephalosporin C zinc salt, cephalothin, cephapirin;        and    -   (iii) other β-lactams, such as monobactams (e.g. aztreonam),        carbapenems (e.g. imipenem (optionally in combination with a        renal enzyme inhibitor such as cilastatin), meropenem,        ertapenem, doripenem (S-4661) and RO4908463 (CS-023)), penems        (e.g. faropenem) and 1-oxa-β-lactams (e.g. moxalactam).-   (b) Tetracyclines, such as tetracycline, demeclocycline,    doxycycline, lymecycline, minocycline, oxytetracycline,    chlortetracycline, meclocycline and methacycline, as well as    glycylcyclines (e.g. tigecycline).-   (c) Aminoglycosides, such as amikacin, gentamicin, netilmicin,    neomycin, streptomycin, tobramycin, amastatin, butirosin, butirosin    A, daunorubicin, dibekacin, dihydrostreptomycin, G 418, hygromycin    B, kanamycin B, kanamycin, kirromycin, paromomycin, ribostamycin,    sisomicin, spectinomycin, streptozocin and thiostrepton.-   (d)    -   (i) Macrolides, such as azithromycin, clarithromycin,        erythromycin, roxithromycin, spiramycin, amphotericins B (e.g.        amphotericin B), bafilomycins (e.g. bafilomycin A1), brefeldins        (e.g. brefeldin A), concanamycins (e.g. concanamycin A), filipin        complex, josamycin, mepartricin, midecamycin, nonactin,        nystatin, oleandomycin, oligomycins (e.g. oligomycin A,        oligomycin B and oligomycin C), pimaricin, rifampicin,        rifamycin, rosamicin, tylosin, virginiamycin and fosfomycin.    -   (ii) Ketolides such as telithromycin and cethromycin (ABT-773).    -   (iii) Lincosamines, such as lincomycin.-   (e) Clindamycin and clindamycin 2-phosphate.-   (f) Phenicols, such as chloramphenicol and thiamphenicol.-   (g) Steroids, such as fusidic acid (optionally in metal salt form,    e.g. in salt form with an alkali metal such as sodium).-   (h) Glycopeptides such as vancomycin, teicoplanin, bleomycin,    phleomycin, ristomycin, telavancin, dalbavancin and oritavancin.-   (i) Oxazolidinones, such as linezolid and AZD2563.-   (j) Streptogramins, such as quinupristin and dalfopristin, or a    combination thereof.-   (k)    -   (i) Peptides, such as polymyxins (e.g. colistin and polymyxin        B), lysostaphin, duramycin, actinomycins (e.g. actinomycin C and        actinomycin D), actinonin, 7-aminoactinomycin D, antimycin A,        antipain, bacitracin, cyclosporin A, echinomycin, gramicidins        (e.g. gramicidin A and gramicidin C), myxothiazol, nisin,        paracelsin, valinomycin and viomycin.    -   (ii) Lipopeptides, such as daptomycin.    -   (iii) Lipoglycopeptides, such as ramoplanin.-   (l) Sulfonamides, such as sulfamethoxazole, sulfadiazine,    sulfaquinoxaline, sulfathiazole (which latter two agents are    optionally in metal salt form, e.g. in salt form with an alkali    metal such as sodium), succinylsulfathiazole, sulfadimethoxine,    sulfaguanidine, sulfamethazine, sulfamonomethoxine, sulfanilamide    and sulfasalazine.-   (m) Trimethoprim, optionally in combination with a sulfonamide, such    as sulfamethoxazole (e.g. the combination co-trimoxazole).-   (n) Antituberculous drugs, such as isoniazid, rifampicin, rifabutin,    pyrazinamide, ethambutol, streptomycin, amikacin, capreomycin,    kanamycin, quinolones (e.g. those at (q) below), para-aminosalicylic    acid, cycloserine and ethionamide.-   (o) Antileprotic drugs, such as dapsone, rifampicin and clofazimine.-   (p)    -   (i) Nitroimidazoles, such as metronidazole and timidazole.    -   (ii) Nitrofurans, such as nitrofurantoin.-   (q) Quinolones, such as nalidixic acid, norfloxacin, ciprofloxacin,    ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin,    garenoxacin, DX-619, WCK 771 (the arginine salt of    S-(−)-nadifloxacin), 8-quinolinol, cinoxacin, enrofloxacin,    flumequine, lomefloxacin, oxolinic acid and pipemidic acid.-   (r) Amino acid derivatives, such as azaserine, bestatin,    D-cycloserine, 1,10-phenanthroline, 6-diazo-5-oxo-L-norleucine and    L-alanyl-L-1-aminoethyl-phosphonic acid.-   (s) Aureolic acids, such as chromomycin A3, mithramycin A and    mitomycin C.-   (t) Benzochinoides, such as herbimycin A.-   (u) Coumarin-glycosides, such as novobiocin.-   (v) Diphenyl ether derivatives, such as irgasan.-   (w) Epipolythiodixopiperazines, such as gliotoxin from Gliocladium    fimbriatum.-   (x) Fatty acid derivatives, such as cerulenin.-   (y) Glucosamines, such as 1-deoxymannojirimycin, 1-deoxynojirimycin    and N-methyl-1-deoxynojirimycin.-   (z) Indole derivatives, such as staurosporine.-   (aa) Diaminopyrimidines, such as iclaprim (AR-100).-   (ab) Macrolactams, such as ascomycin.-   (ac) Taxoids, such as paclitaxel.-   (ad) Statins, such as mevastatin.-   (ae) Polyphenolic acids, such as (+)-usnic acid.-   (af) Polyethers, such as lasalocid A, lonomycin A, monensin,    nigericin and salinomycin.-   (ag) Picolinic acid derivatives, such as fusaric acid.-   (ah) Peptidyl nucleosides, such as blasticidine S, nikkomycin,    nourseothricin and puromycin.-   (ai) Nucleosides, such as adenine 9-β-D-arabinofuranoside,    5-azacytidine, cordycepin, formycin A, tubercidin and tunicamycin.-   (aj) Pleuromutilins, such as GSK-565154, GSK-275833 and tiamulin.-   (ak) Peptide deformylase inhibitors, such as LBM415 (NVP PDF-713)    and BB 83698.-   (al) Antibacterial agents for the skin, such as fucidin, benzamycin,    clindamycin, erythromycin, tetracycline, silver sulfadiazine,    chlortetracycline, metronidazole, mupirocin, framycitin, gramicidin,    neomycin sulfate, polymyxins (e.g. polymixin B) and gentamycin;-   (al) Miscellaneous agents, such as methenamine (hexamine),    doxorubicin, piericidin A, stigmatellin, actidione, anisomycin,    apramycin, coumermycin A1, L(+)-lactic acid, cytochalasins (e.g.    cytochalasin B and cytochalasin D), emetine and ionomycin.

Particular conventional antibiotics that may be mentioned include thoselisted at (a) to (q) above, such as:

-   -   the -cillins listed at (a)(i) above (e.g. amoxicillin,        ampicillin, phenoxymethylpenicillin or, particularly,        co-amoxiclav (co-amoxicillin));    -   the cephalosporins listed at (a)(ii) above (e.g. cefuroxime,        cefaclor or cefalexin);    -   the carbapenems listed at (a)(iii) above (e.g. ertapenem);    -   the tetracyclines listed at (b) above (e.g. doxycycline or        minocycline);    -   the macrolides listed at (d)(i) above (e.g. clarithromycin,        erythromycin, roxithromycin or, particularly, azithromycin);    -   the ketolides listed at (d) (ii) above (e.g. telithromycin);    -   the oxazolidinones listed at (i) above (e.g. linezolid);    -   the lipopeptides listed at (k)(ii) above (e.g. daptomycin)    -   trimethoprim and the combinations therewith (e.g. co-trimoxazol)        listed at (m) above;    -   the nitrofurans listed at (p) above (e.g. nitrofurantoin); and    -   the quinolones listed at (q) above (e.g. norfloxacin,        ciprofloxacin, ofloxacin, or, particularly, levofloxacin or        moxifloxacin).

When used herein, the term “conventional antifungal agent(s)” includereferences to fungicidal and fungistatic agents that are known in theprior art (i.e. agents that have been selected and developed on thebasis of their MICs—namely their ability to inhibit the growth offungi). In this respect, particular conventional antifungal agents thatmay be mentioned include any one or more of the following.

-   -   (a) azole antifungals, such as imidazoles (e.g. clotrimazole,        econazole, fenticonazole, ketoconazole, miconazole, sulconazole,        and tioconazole) or triazoles (e.g. fluconazole, itraconazole        and voriconazole);    -   (b) polyene antifungals, such as amphotericin and nystatin;    -   (c) miscellaneous antifungal agents such as griseofulvin,        caspofungin or flucytosine, which latter two agents are        optionally employed in combination;    -   (d) allylamine antifungals, such as terbinafine.

Compounds of formula I that may be mentioned include the following.

-   -   (l) A compound of formula I, as hereinbefore defined, provided        that the compound is not of the formula

in which:

-   -   (a) R^(y) represents H and R^(x) represents H, methyl,        2-hydroxyethyl, phenyl, 4-methylphenyl, 4-methoxyphenyl or        2-chlorophenyl;    -   (b) R^(y) represents methoxy and R^(x) represents phenyl; or    -   (c) R^(y) represents hydroxy and R^(x) represents methyl,        2-hydroxyethyl or phenyl.    -   (In other words, the compound is not:

-   4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   1,4-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   1-[2-hydroxyethyl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   4-methyl-1-(4-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   4-methyl-1-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   4-methyl-1-(2-chlorophenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   6-methoxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   6-hydroxy-1,4-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

-   6-hydroxy-1-[2-hydroxyethyl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;    or

-   6-hydroxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline.)

-   (2) A compound of formula I, as hereinbefore defined, provided that    R³ does not represent H or a single OR^(7a) substituent at the    6-position of the pyrrolo[3,2-c]quinoline or    2,3-dihydro-1H-pyrrolo[3,2-c]quino line ring system, wherein R^(7a)    either:    -   (a) is as hereinbefore defined;    -   (b) represents H or C₁₋₁₀ alkyl; or    -   (c) represents H or methyl.

-   (3) A compound of formula I, as hereinbefore defined, in which X    represents —C(R^(8a))(R^(8b))—C(R^(8c))(R^(8d))—, wherein R^(8a) to    R^(8d) are as hereinbefore defined.

Particular embodiments of the compounds of formula I include those inwhich:

-   (1) R¹ represents    -   C₁₋₆ alkyl or C₃₋₇ cycloalkyl (which latter two groups are        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl, C₃₋₆ cycloalkyl (which latter group is        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(4a), C(O)OR^(4i), aryl        and Het¹) (such as C₁₋₆ alkyl or C₃₋₇ cycloalkyl (which latter        two groups are optionally substituted by one or more        substituents selected from halo, C₁₋₄ alkyl, C₃₋₆ cycloalkyl        (which latter group is optionally substituted by one or more        substituents selected from halo, C₁₋₄ alkyl and C₁₋₄ alkoxy),        OR^(4a), aryl and Het¹),    -   aryl or    -   Het²;-   (2) R² represents C₁₋₆ alkyl optionally substituted by one or more    substituents selected from halo, OR^(5a), N(R^(5g))(R^(5h)) and    C(O)OR^(5i);-   (3) R³ represents H or, particularly, one to four substituents on    the fused benzene ring selected from    -   halo (e.g. chloro),    -   CN,    -   C₁₋₆ alkyl optionally substituted by one or more substituents        selected from halo, CN, and OR^(6a),    -   OR^(7a),    -   S(O)_(r)R^(7b),    -   N(H)R^(7h),    -   C(O)R^(7i),    -   C(O)OR^(7i),    -   aryl and    -   Het⁶    -   (e.g. R³ represents one to four substituents on the fused        benzene ring selected from C₁₋₆ alkyl (optionally substituted by        one or more substituents selected from halo, CN, and OR^(6a)),        OR^(7a), S(O)_(r)R^(7b), aryl and Het⁶);-   (4) R^(4a) to R^(4i), R^(5a) to R^(5i), R^(6a) to R^(6i) and R^(7a)    to R^(7i) independently represent, at each occurrence,    -   C₁₋₁₀ alkyl (optionally substituted by one or more substituents        selected from halo and aryl),    -   C₃₋₆ cycloalkyl (optionally substituted by one or more        substituents selected from halo, C₁₋₄ alkyl and C₁₋₄ alkoxy),    -   aryl or    -   Het⁹,    -   or R^(4a) to R^(4i), R^(5a) to R^(5i), R^(6a) to R^(6i) and        R^(7c) to R^(7i) may also represent H,    -   provided that R^(4b), R^(5b), R^(6b) or R^(7b) does not        represent H when n, p, q or r, respectively is 1 or 2;-   (5) X represents —C(H)R^(8a)—C(H)R^(8c)—;-   (6) R^(8a) to R^(8f) independently represent H or methyl;-   (7) each aryl independently represents a C₆₋₁₀ carbocyclic aromatic    group, which group may comprise either one or two rings and may be    substituted by one or more substituents selected from    -   halo,    -   CN,    -   C₁₋₆ alkyl optionally substituted by one or more substituents        selected from halo, C₃₋₆ cycloalkyl (which latter groups is        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(9a), S(O)_(t)R^(9b),        S(O)₂N(H)R^(9c), N(H)S(O)₂R^(9f), N(R^(9g))(R^(9h)),        B⁹—C(O)—B¹⁰—R^(9i), phenyl (which latter groups is optionally        substituted by one or more substituents selected from OH, halo,        methyl and methoxy) and Het¹⁰,    -   OR^(10a),    -   S(O)_(u)R^(10b),    -   N(R^(10g))(R^(10h)),    -   B¹¹—C(O)—B¹²—R^(10i),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄        alkoxy) or    -   Het¹¹;-   (8) R^(9a) to R^(9i) and R^(10a) to R^(10i) independently represent,    at each occurrence,    -   H,    -   C₁₋₆ alkyl, C₃₋₆ cycloalkyl (which latter two groups are        optionally substituted by one or more substituents selected from        halo, OH, C₁₋₄ alkyl, C₄₋₆ cycloalkyl (which latter group is        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), C₁₋₄ alkoxy, NH₂, N(H)—C₁₋₄        alkyl, N(C₁₋₄ alkyl)₂, phenyl (which latter group is optionally        substituted by one or more substituents selected from OH, halo,        methyl and methoxy) and Het¹²),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from OH, halo, C₁₋₄ alkyl and        C₁₋₄alkoxy) or Het¹³,    -   provided that R^(9b) or R^(10b) does not represent H when t or        u, respectively is 1 or 2;-   (9) Het¹ to Het¹³ independently represent 5- to 10-membered    heterocyclic groups containing from one to four heteroatoms selected    from oxygen, nitrogen and/or sulfur, which heterocyclic groups may    comprise one or two rings and may be substituted by one or more    substituents selected from    -   halo,    -   C₁₋₆ alkyl, C₃₋₆ cycloalkyl, which latter two groups are        optionally substituted by one or more substituents selected from        halo, OH, C₁₋₄ alkyl, C₄₋₆ cycloalkyl (which latter group is        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), C₁₋₄ alkoxy, phenyl (which        latter group is optionally substituted by one or more        substituents selected from OH, halo, methyl and methoxy) and        Het^(a),    -   OR^(12a),    -   ═O,    -   S(O)_(w)R^(12b),    -   N(R^(12g))(R^(12h)),    -   B¹⁵—C(O)—B¹⁶—R^(12i),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from OH, halo, methyl and methoxy) or    -   Het^(b);-   (10) R^(11a) to R^(11i) and R^(12a) to R^(12i) independently    represent, at each occurrence,    -   H,    -   C₁₋₆ alkyl, C₃₋₆ cycloalkyl (which latter two groups are        optionally substituted by one or more substituents selected from        halo, OH, C₁₋₄ alkyl, C₄₋₆ cycloalkyl (which latter group is        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), C₁₋₄ alkoxy, phenyl (which        latter group is optionally substituted by one or more        substituents selected from OH, halo, methyl and methoxy) and        Het^(c),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from OH, halo, methyl and methoxy) or    -   Het^(d),    -   provided that R^(11b) or R^(12b) does not represent H when v or        w, respectively is 1 or 2;-   (11) B¹ to B¹⁶ independently represent a direct bond, O, S or NH;-   (12) R¹³ represents C₁₋₄ alkyl or phenyl (which latter group is    optionally substituted by one or more substituents selected from OH,    halo, methyl and methoxy);-   (13) Het^(a) to Het^(e) independently represent 5- or 6-membered    heterocyclic groups containing one or heteroatoms selected from    oxygen, nitrogen and/or sulfur, which heterocyclic groups may be    substituted by one or more substituents selected from halo, ═O and    methyl;-   (14) unless otherwise specified, alkyl, alkenyl, alkynyl,    cycloalkyl, and cycloalkenyl groups, as well as the alkyl part of    alkoxy groups, are unsubstituted;-   (15) unless otherwise specified, cycloalkyl groups comprise one or    (if sufficient number of C-atoms is present) two rings and are    optionally ring-fused to a benzene ring (so as to form a group such    as, for example, 1,2,3,4-tetrahydronaphthyl or, particularly,    indanyl).

More particular embodiments of the compounds of formula I include thosein which:

-   (1) R¹ represents    -   C₁₋₅ alkyl (which latter group is optionally substituted by one        or more substituents selected from fluoro, C₃₋₅ cycloalkyl        (which latter group is optionally substituted by one or more        substituents selected from fluoro, methyl and methoxy), C₁₋₄        alkoxy (e.g. methoxy), phenoxy, phenyl (which latter group is        optionally substituted by one or more substituents selected from        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy) and Het¹),    -   C₃₋₆ cycloalkyl, (which latter group is optionally fused to a        benzene ring (e.g. to form a group such as indanyl or        1,2,3,4-tetrahydronaphthyl) and is optionally substituted by one        or more substituents selected from fluoro, methyl and methoxy),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from halo, C₁₋₆ alkyl (which latter        group is optionally substituted by one or more substituents        selected from OR^(9a), N(R^(9g))(R^(9h)) and phenyl), OR^(10a)        and Het¹¹), or    -   Het²;-   (2) Het¹ represents 5- to 10-membered, aromatic or part-aromatic    heterocyclic group containing from one to four heteroatoms selected    from oxygen, nitrogen and/or sulfur, which heterocyclic group    comprises either one or two rings and is optionally substituted by    one or more substituents selected from halo, C₁₋₃ alkyl (e.g.    methyl) and C₁₋₃ alkoxy (e.g. methoxy) (e.g. Het¹ represents a 9- or    10-membered, aromatic or part-aromatic heterocyclic group containing    one or two heteroatoms selected from oxygen and nitrogen, such as a    benzodioxanyl or benzodioxolyl group);-   (3) Het² represents a 5- to 10-membered, heterocyclic group    containing from one to four heteroatoms selected from oxygen,    nitrogen and/or sulfur, which heterocyclic group comprises either    one or two rings and is optionally substituted by one or more    substituents selected from halo, C₁₋₃ alkyl (which latter group is    optionally substituted by phenyl) and OR^(12a) (e.g. Het² represents    a 5- or 6-membered, aromatic or fully saturated heterocyclic group    containing one or two heteroatoms selected from oxygen and nitrogen,    such as a pyridyl or piperidinyl group, which group is optionally    substituted by C₁₋₂ alkyl (which latter group is optionally    substituted by phenyl), C₁₋₃ alkoxy (e.g. methoxy) or phenoxy);-   (4) Het¹¹ represents a 5- to 6-membered, fully saturated, partly    unsaturated or aromatic heterocyclic group containing one or two    heteroatoms selected from oxygen, nitrogen and/or sulfur, which    heterocyclic group is optionally substituted by one or more    substituents selected from halo and C₁₋₃ alkyl (e.g. Het¹¹    represents a 6-membered, fully saturated heterocyclic group    containing one or two heteroatoms selected from oxygen and nitrogen,    such as a piperazinyl group, which group is optionally substituted    by C₁₋₃ alkyl (e.g. methyl));-   (5) R^(9a) to R^(9i) independently represent, at each occurrence, H    or C₁₋₃ alkyl (e.g. methyl);-   (6) R^(10a) represents, independently at each occurrence,    -   H,    -   C₁₋₄ alkyl, C₅₋₆ cycloalkyl (which latter two groups are        optionally substituted by one or more substituents selected from        halo, methyl, methoxy, NH₂, N(H)CH₃, N(CH₃)₂ or phenyl),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from halo, methyl and methoxy) or    -   Het¹³;-   (7) Het¹³ represents a 5- to 10-membered, aromatic heterocyclic    group containing from one to four heteroatoms selected from oxygen,    nitrogen and/or sulfur, which heterocyclic group comprises either    one or two rings and is optionally substituted by one or more    substituents selected from halo, C₁₋₃ alkyl (e.g. methyl) and C₁₋₃    alkoxy (e.g. methoxy) (e.g. Het² represents a 5- or 6-membered,    aromatic heterocyclic group containing one or two heteroatoms    selected from oxygen and nitrogen, such as an unsubstituted pyridyl    group);-   (7) R^(12a) represents C₁₋₆ alkyl, C₅₋₆ cycloalkyl (which latter two    groups are optionally substituted by one or more substituents    selected from halo, methyl and methoxy) or phenyl (which latter    group is optionally substituted by one or more substituents selected    from halo, methyl and methoxy);-   (8) R² represents C₁₋₃ alkyl optionally substituted by one or more    substituents selected from halo, OH and N(H)R^(59g) (e.g. R²    represents unsubstituted C₁₋₃ alkyl, such as methyl);-   (9) R³ represents one to three (e.g. one or two) substituents on the    fused benzene ring selected from    -   C₁₋₃ alkyl (optionally substituted by one or more halo groups),    -   N(H)R^(7h),    -   Het⁶ or, particularly,    -   OR^(7a)    -   (such as one to three (e.g. one or two) substituents on the        fused benzene ring selected from C₁₋₃ alkyl (optionally        substituted by one or more halo groups) or, particularly,        OR^(7a));-   (10) R^(7a) represents, independently at each occurrence,    -   C₁₋₆ alkyl (optionally substituted by one or more substituents        selected from halo and phenyl (which latter group is optionally        substituted by one or more substituents selected from halo, C₁₋₄        alkyl and C₁₋₄ alkoxy)),    -   C₅₋₆ cycloalkyl (optionally substituted by one or more        substituents selected from halo, methyl and methoxy),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from halo, C₁₋₄ alkyl and C₁₋₄        alkoxy) or    -   Het⁹;-   (11) R^(7a) represents phenyl optionally substituted by one or more    substituents selected from halo, C₁₋₄ alkyl and C₁₋₄ alkoxy);-   (12) Het⁶ represents a 5- or 6-membered fully saturated heterocyclic    group containing one or two heteroatoms selected from oxygen and    nitrogen (e.g. a piperidinyl (such as a piperidin-1-yl) group),    which group is optionally substituted by one or more C₁₋₂ alkyl    groups;-   (13) Het⁹ represents a 5- to 10-membered, aromatic heterocyclic    group containing from one to four heteroatoms selected from oxygen,    nitrogen and/or sulfur, which heterocyclic group comprises either    one or two rings and is optionally substituted by one or more    substituents selected from halo, C₁₋₃ alkyl (e.g. methyl) and C₁₋₃    alkoxy (e.g. methoxy);-   (14) X represents —CH₂—CH₂—.

In one particular embodiment of the invention, the compound of formula Imay be represented as a compound of formula Ia,

wherein R¹ and R² are as hereinbefore defined and each of R^(3a) toR^(3d) represents either H or a substituent as hereinbefore defined inrelation to the group R³.

Hereinafter, references to compounds of formula I are, unless thecontext indicates otherwise, intended to include references to compoundsof formula Ia. Conversely, where reference is made to particularembodiments of the compounds of formula Ia, these embodiments applyequally, where relevant, to compounds of formula I.

Particular embodiments of the compounds of formula Ia that may bementioned include those in which:

-   (1) one or both of R^(3a) and R^(3c) represent a substituent as    hereinbefore defined in relation to the group R³, and R^(3b) and    R^(3d) both represent H;-   (2) R^(3a) and R^(3c) independently represent H, OR^(7a), N(H)R^(7h)    or Het⁶ (e.g. H or OR^(7a)), wherein R^(7a), R^(7h) and Het⁶ are as    hereinbefore defined, provided that R^(3a) and R^(3c) do not both    represent H.

More particular embodiments of the compounds of formula Ia that may bementioned include those in which:

-   R¹ represents    -   C₁₋₅ alkyl (which latter group is optionally substituted by C₃₋₅        cycloalkyl (e.g. cyclopropyl), phenyl (which latter group is        optionally substituted by one or more substituents selected from        halo, methyl and methoxy), phenoxy, benzodioxanyl (e.g.        benzodioxan-2-yl) or benzodioxolyl (e.g. benzodioxol-5-yl)),    -   C₃₋₆ cycloalkyl (which latter group is optionally fused to a        benzene ring (e.g. to provide a cycloalkyl group such as        cyclopropyl, or a benzo-fused cycloalkyl group such as        1,2,3,4-tetrahydronaphthyl or indanyl (e.g. indan-2-yl,        indan-1-yl, (S)-indan-1-yl or (R)-indan-1-yl))),    -   phenyl (which latter group is optionally substituted by one or        more substituents (e.g. one or two substituents, such as a        single substituent in the 4-position) selected from halo (e.g.        fluoro), C₁₋₄ alkyl (e.g. methyl or, particularly, iso-propyl),        OH, C₁₋₄ alkoxy (which latter group is optionally substituted by        N(CH₃)₂, providing, for example, a methoxy or OCH₂CH₂N(CH₃)₂        group), phenoxy (which latter group is either unsubstituted or        is substituted by one or more, e.g. one or two, substituents        selected from methoxy or, particularly, halo (such as fluoro)),        pyridyloxy (e.g. pyrid-3-yloxy) and piperazinyl (optionally        substituted by methyl, providing, for example,        4-methylpiperazin-1-yl),    -   pyridyl (e.g. pyrid-3-yl), which latter group is optionally        substituted (e.g. in the 6-position) by methoxy or phenoxy, or        piperidinyl (e.g. piperidin-4-yl), which latter group is        optionally substituted (e.g. at the 1-position) by C₁₋₂ alkyl        (which latter group is optionally substituted by phenyl,        providing, for example, benzyl);

R^(3a) and R^(3a) independently represent

-   -   H,    -   C₁₋₄ alkoxy (optionally substituted by one or more halo atoms        (e.g. to provide a substituted alkoxy group such as        trifluoromethoxy or, particularly, an unsubstituted alkoxy group        such as methoxy or ethoxy)),    -   —N(H)-(phenyl), the phenyl part of which latter group is        (optionally substituted by one or more substituents selected        from halo, methyl and methoxy),    -   a 5- or 6-membered N-linked, fully saturated heterocycle        containing an N-atom (that via which the group is linked) and        optionally containing one further heteroatom selected from N and        O (e.g. a piperidin-1-yl group) or    -   phenoxy (optionally substituted by one or more substituents        selected from halo, methyl and methoxy), (e.g. R^(3a) and R^(3c)        independently represent H, C₁₋₄ alkoxy (optionally substituted        by one or more halo atoms (e.g. to provide a substituted alkoxy        group such as trifluoromethoxy or, particularly, an        unsubstituted alkoxy group such as methoxy or ethoxy)), or        phenoxy (optionally substituted by one or more substituents        selected from halo, methyl and methoxy)),        provided that R^(3a) and R^(3c) do not both represent H.

Further, in compounds of formula Ia, embodiments of the group R¹ thatmay be mentioned include phenyl substituted (e.g. at the 4-position) bya C₃₋₁₂ alkyl group (e.g. a branched C₃₋₁₂ alkyl group, such asiso-propyl), and optionally further substituted as defined above inrespect of R¹ (when that group represents aryl).

Specific embodiments of the compounds of formula Ia that may bementioned further include those in which:

-   (1) R^(3a) and R^(3c) are both other than H (e.g. R^(3a) and R^(3c)    both represent OR^(7a), wherein R^(7a) is as hereinbefore defined),    and R^(3b) and R^(3d) both represent H;-   (2) R^(3a) is other than H (e.g. R^(3a) represents OR^(7a), wherein    R^(7a) is as hereinbefore defined), and R^(3b), R^(3c) and R^(3d)    all represent H; or, particularly,-   (3) R^(3c) is other than H (e.g. R^(3c) represents OR^(7a), wherein    R^(7a) is as hereinbefore defined), and R^(3a), R^(3c) and R^(3d)    all represent H.

Specific values of R¹ that may be mentioned in relation to compounds offormula I include 3-methylbut-1-yl, 1-methylbenzimidazol-2-yl,cyclopropyl, cyclopropylmethyl, 2-phenoxyethyl, benzodioxol-5-ylmethyl,6-methoxypyridin-3-yl, 6-phenoxypyridin-3-yl, 3-hydroxyphenyl,3-hydroxy-5-methylphenyl, 4-hydroxyphenyl,4-(2-dimethylaminoethoxy)phenyl,3-fluoro-4-(4-methylpiperazin-1-yl)phenyl, 4-(pyridin-3-yloxy)phenyl or,particularly, benzodioxan-2-ylmethyl, 1-benzylpiperidin-4-yl,cyclohexyl, 1,2,3,4-tetrahydronaphth-1-yl, 1-phenylethyl, 2-phenylethyl,phenyl, 4-iso-propylphenyl, 4-methoxyphenyl, 3-phenoxyphenyl,4-phenoxyphenyl, benzyl, (2-methylphenyl)methyl, indan-1-yl orindan-2-yl.

Other specific values of R¹ that may be mentioned in relation tocompounds of formula I include 3-methoxypropyl, ethoxycarbonylmethyl,2-(methoxycarbonyl)ethyl, 2-(ethoxycarbonyl)ethyl,3-(methoxycarbonyl)propyl, 3-(ethoxycarbonyl)propyl,1-benzylpyrrolidin-3-yl, 1-methylpiperidin-4-yl,tetrahydrofuran-2-ylmethyl, 2-pyridylmethyl, 5-methylpyrazin-2-ylmethyl,2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 3-(1-pyrrolidin-2-onyl)propyl,2-methylphenyl, 4-(piperidin-1-yl)phenyl, 4-(3-pyridyl)phenyl,2-phenylpropyl or, particularly, (S)-indan-1-yl, (R)-indan-1-yl,2-(4-chlorophenyl)ethyl, 2-(4-methoxyphenyl)ethyl or4-(4-fluorophenoxy)phenyl.

Particular compounds of formula Ia that may be mentioned include thoseof the following formula,

wherein:

R¹ and R² are as hereinbefore defined;

R^(3a1) represents H and R^(3c1) represents phenoxy, or, when R¹represents

-   -   C₁₋₂ alkyl substituted by optionally substituted phenyl (e.g.        benzyl, (2-methylphenyl)methyl, 1-phenylethyl or, particularly,        2-phenylethyl),    -   C₅₋₆ cycloalkyl fused to a benzene ring (e.g.        1,2,3,4-tetrahydronaphthyl, indan-1-yl or, particularly,        indan-2-yl), or    -   phenyl substituted by phenoxy,        then R^(3a1) can additionally represent methoxy, or phenoxy and        R^(3c1) can additionally represent H, methoxy, trifluoromethoxy        or ethoxy,        provided that R^(3a1) and R^(3c1) do not both represent phenoxy.

The medicament mentioned in the first aspect of the invention may beutilised in a method of medical treatment. Thus, according to a secondaspect of the invention, there is provided a method of killingclinically latent microorganisms in a mammal infected with such latentmicroorganisms, the method comprising administering to said mammal amicrobicidally effective amount of compound of formula I, ashereinbefore defined.

Furthermore, the compound of formula I may be used to kill clinicallylatent microorganisms. Thus, according to a third aspect of theinvention, there is provided the use of a compound of formula I, ashereinbefore defined, to kill clinically latent microorganisms. In oneembodiment, the use according to this aspect of the invention is an exvivo use.

In addition to killing clinically latent microorganisms, the inventorshave discovered that compounds of formula I are able to killmicroorganisms of many different phenotypes, including growingmicroorganisms.

In this respect, fourth, fifth and sixth aspects of the inventionprovide, respectively:

-   (a) the use of a compound of formula I, as hereinbefore defined, for    the preparation of a medicament for the treatment of a microbial    infection;-   (b) a method of treating or preventing a microbial infection in a    mammal, the method comprising administering to said mammal an    antimicrobially effective amount of a compound of formula I, as    hereinbefore defined;-   (c) use (e.g. ex vivo use) of a compound of formula I to kill    microorganisms.

For the avoidance of doubt, as used herein, the term “treatment”includes therapeutic and/or prophylactic treatment.

In the fourth to sixth aspects of the invention, it is preferred thatthe compound of formula I is not:

-   (i) 1,4-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (ii)    1-[2-hydroxyethyl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (iii) 4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (iv)    4-methyl-1-(4-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (v)    4-methyl-1-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (vi)    4-methyl-1-(2-chlorophenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (vii)    6-methoxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (viii)    6-hydroxy-1,4-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (ix)    6-hydroxy-1-[2-hydroxyethyl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;    or-   (x)    6-hydroxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline.

As mentioned above, the uses according to the third and sixth aspects ofthe invention may be ex vivo uses, such as the use of a compound offormula I, as hereinbefore defined:

-   (a) as a sterilising agent; or-   (b) as a preservative.

Conversely, the compounds of formula I may be employed in methods ofsterilisation or preservation, such as:

-   (i) a method of sterilising an object, the method comprising    applying to said object a compound of formula I, as hereinbefore    defined; or-   (ii) a method of preserving an inorganic or, preferably, an organic    material, said method comprising contacting, combining or mixing    said material with a compound of formula I, as hereinbefore defined.

In relation to the method described at (i) above, the object ispreferably other than a human or animal body. Further, the materialsthat may be preserved according to the method described at (ii) aboveinclude polymers, lubricants, paints, fibres, leather, paper,foodstuffs, water and aqueous mixtures and solutions.

When used to kill clinically latent microorganisms or to treat amicrobial infection, the compounds of formula I may be used either alone(i.e. as sole microbicidal or antimicrobial agents) or in combinationwith any one or more of the conventional antimicrobial agents describedabove.

Further, when used as a sterilising agent, the compounds of formula Imay be used either alone or in combination with a conventionalsterilising agent. The term “conventional sterilising agent”, when usedherein, includes references to alcohols (e.g. industrial methylatedspirits or ethanol), sodium chloride, thymol, chlorhexidine, cationicsurfactants (e.g. cetrimide), iodine (optionally combined withpovidone), phenolics (e.g. triclosan), oxidants (e.g. hydrogen peroxide,potassium permanganate or sodium hypochlorite) and any one or more ofthe conventional antimicrobial agents described above.

Thus, according to seventh and eighth aspects of the invention, there isprovided, respectively:

-   (i) a combination product comprising    -   (A) a compound of formula I, as hereinbefore defined, and    -   (B) a conventional antibiotic agent, as hereinbefore defined,        wherein each of components (A) and (B) is formulated in        admixture with a pharmaceutically-acceptable adjuvant, diluent        or carrier; and-   (b) a formulation comprising a compound of formula I, as    hereinbefore defined and a conventional sterilising agent, as    hereinbefore defined, or a salt and/or solvate thereof.

The combination product according to the seventh aspect of the inventionprovides for the administration of component (A) in conjunction withcomponent (B), and may thus be presented either as separateformulations, wherein at least one of those formulations comprisescomponent (A) and at least one comprises component (B), or may bepresented (i.e. formulated) as a combined preparation (i.e. presented asa single formulation including component (A) and component (B)).

Thus, there is further provided:

-   (1) a pharmaceutical formulation including a compound of formula I,    as hereinbefore defined and a conventional antimicrobial agent, as    hereinbefore defined, or a pharmaceutically-acceptable derivative    thereof, in admixture with a pharmaceutically-acceptable adjuvant,    diluent or carrier (which formulation is hereinafter referred to as    a “combined preparation”); and-   (2) a kit of parts comprising components:    -   (I) a pharmaceutical formulation including a compound of formula        I, as hereinbefore defined, in admixture with a        pharmaceutically-acceptable adjuvant, diluent or carrier; and    -   (II) a pharmaceutical formulation including a conventional        antimicrobial agent, as hereinbefore defined, or a        pharmaceutically-acceptable derivative thereof, in admixture        with a pharmaceutically-acceptable adjuvant, diluent or carrier,    -   which components (I) and (II) are each provided in a form that        is suitable for administration in conjunction with the other.

Component (I) of the kit of parts is thus component (A) in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier.Similarly, component (II) is component (B) in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.

According to a ninth aspect of the invention, there is provided a methodof making a kit of parts as defined above, which method comprisesbringing a component (I), as defined above, into association with acomponent (II), as defined above, thus rendering the two componentssuitable for administration in conjunction with each other.

By bringing the two components “into association with” each other, weinclude that components (I) and (II) of the kit of parts may be:

-   (i) provided as separate formulations (i.e. independently of one    another), which are subsequently brought together for use in    conjunction with each other in combination therapy; or-   (ii) packaged and presented together as separate components of a    “combination pack” for use in conjunction with each other in    combination therapy.

Thus, there is further provided a kit of parts comprising:

-   (1) one of components (I) and (II) as defined herein; together with-   (2) instructions to use that component in conjunction with the other    of the two components.

The kits of parts described herein may comprise more than oneformulation including an appropriate quantity/dose of component (A),and/or more than one formulation including an appropriate quantity/doseof component (B), in order to provide for repeat dosing. If more thanone formulation (comprising either active compound) is present, suchformulations may be the same, or may be different in terms of the doseof component (A) or component (B), chemical composition and/or physicalform.

The combination product according to the seventh aspect of the inventionmay be used to kill clinically latent microorganisms and/or treat amicrobial infection. Thus, further aspects of the invention provide:

-   (i) the use of a combination product according to the seventh aspect    of the invention for the preparation of a medicament for killing    clinically latent microorganisms;-   (ii) a method of killing clinically latent microorganisms in a    mammal, the method comprising administering to said mammal a    microbicidally effective amount of a combination product according    to the seventh aspect of the invention;-   (iii) the use of a combination product according to the seventh    aspect of the invention for the preparation of a medicament for    treating a microbial infection; and-   (iv) a method of treating or preventing a microbial infection in a    mammal, the method comprising administering to said mammal an    antimicrobially effective amount of a combination product according    to the seventh aspect of the invention.

The method of (iv) above provides for the advantage that the amount ofconventional antimicrobial agent required to treat the microbialinfection is reduced compared to that required in the absence of acompound of formula I.

When used herein, the terms “bacteria” (and derivatives thereof, such as“bacterial infection”) includes references to organisms (or infectionsdue to organisms) of the following classes and specific types:

-   -   Gram-positive cocci, such as        -   Staphylococci (e.g. Staph. aureus, Staph. epidermidis,            Staph. saprophyticus, Staph. auricularis, Staph. capitis            capitis, Staph. c. ureolyticus, Staph. caprae, Staph. cohnii            cohnii, Staph. c. urealyticus, Staph. equorum, Staph.            gallinarum, Staph. haemolyticus, Staph. hominis hominis,            Staph. h. novobiosepticius, Staph. hyicus, Staph.            intermedius, Staph. lugdunensis, Staph. pasteuri, Staph.            saccharolyticus, Staph. schleiferi schleiferi, Staph. s.            coagulans, Staph. sciuri, Staph. simulans, Staph. warneri            and Staph. xylosus) and        -   Streptococci (e.g.            -   beta-haemolytic, pyogenic streptococci (such as Strept.                agalactiae, Strept. canis, Strept. dysgalactiae                dysgalactiae, Strept. dysgalactiae equisimilis, Strept.                equi equi, Strept. equi zooepidemicus, Strept. iniae,                Strept. porcinus and Strept. pyogenes),            -   microaerophilic, pyogenic streptococci (Streptococcus                “milleri”, such as Strept. anginosus, Strept.                constellatus constellatus, Strept. constellatus                pharyngidis and Strept. intermedius),            -   oral streptococci of the “mitis”                (alpha-haemolytic—Streptococcus “viridans”, such as                Strept. mitis, Strept. oxalis, Strept. sanguinis,                Strept. cristatus, Strept. gordonii and Strept.                parasanguinis), “salivarius” (non-haemolytic, such as                Strept. salivarius and Strept. vestibularis) and                “mutans” (tooth-surface streptococci, such as Strept.                criceti, Strept. mutans, Strept. ratti and Strept.                sobrinus) groups,            -   Strept. acidominimus, Strept. bovis, Strept. faecalis,                Strept. equinus, Strept. pneumoniae and Strept. suis,        -   or Streptococci alternatively classified as Group A, B, C,            D, E, G, L, P, U or V Streptococcus);    -   Gram-negative cocci, such as Neisseria gonorrhoeae, Neisseria        meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria        flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria        sicca, Neisseria subflava and Neisseria weaveri;    -   Bacillaceae, such as Bacillus anthracis, Bacillus subtilis,        Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus        cereus;    -   Enterobacteriaceae, such as        -   Escherichia coli,        -   Enterobacter (e.g. Enterobacter aerogenes, Enterobacter            agglomerans and Enterobacter cloacae)        -   Citrobacter (such as Citrob. freundii and Citrob. divernis),        -   Hafnia (e.g. Hafnia alvei),        -   Erwinia (e.g. Erwinia persicinus),        -   Morganella morganii,        -   Salmonella (Salmonella enterica and Salmonella typhi),        -   Shigella (e.g. Shigella dysenteriae, Shigella flexneri,            Shigella boydii and Shigella sonnei),        -   Klebsiella (e.g. Klebs. pneumoniae, Klebs. oxytoca, Klebs.            ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs.            terrigena, Klebs. granulomatis (Calymmatobacterium            granulomatis) and Klebs. rhinoscleromatis),        -   Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris),        -   Providencia (e.g. Providencia alcalifaciens, Providencia            rettgeri and Providencia stuartii),        -   Serratia (e.g. Serratia marcescens and Serratia            liquifaciens), and        -   Yersinia (e.g. Yersinia enterocolitica, Yersinia pestis and            Yersinia pseudotuberculosis);    -   Enterococci (e.g. Enterococcus avium, Enterococcus        casseliflavus, Enterococcus cecorum, Enterococcus dispar,        Enterococcus durans, Enterococcus faecalis, Enterococcus        faecium, Enterococcus flavescens, Enterococcus gallinarum,        Enterococcus hirae, Enterococcus malodoratus, Enterococcus        mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and        Enterococcus solitarius);    -   Helicobacter (e.g. Helicobacter pylori, Helicobacter cinaedi and        Helicobacter fennelliae);    -   Acinetobacter (e.g. A. baumanii, A. calcoaceticus, A.        haemolyticus, A. johnsonii, A. junii, A. lwoffi and A.        radioresistens);    -   Pseudomonas (e.g. Ps. aeruginosa, Ps. maltophilia        (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps.        chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps.        monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps.        pseudalcaligenes, Ps. putida and Ps. stutzeri);    -   Bacteriodes fragilis;    -   Peptococcus (e.g. Peptococcus niger);    -   Peptostreptococcus;    -   Clostridium (e.g. C. perfringens, C. difficile, C. botulinum, C.        tetani, C. absonum, C. argentinense, C. baratii, C.        bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C.        carnis, C. celatum, C. clostridioforme, C. cochlearium, C.        cocleatum, C. fallax, C. ghonii, C. glycolicum, C.        haemolyticum, C. hastiforme, C. histolyticum, C. indolis, C.        innocuum, C. irregulare, C. leptum, C. limosum, C.        malenominatum, C. novyi, C. oroticum, C. paraputrificum, C.        piliforme, C. putrefasciens, C. ramosum, C. septicum, C.        sordelii, C. sphenoides, C. sporogenes, C. subterminale, C.        symbiosum and C. tertium);    -   Mycoplasma (e.g. M. pneumoniae, M. hominis, M. genitalium and M.        urealyticum);    -   Mycobacteria (e.g. Mycobacterium tuberculosis, Mycobacterium        avium, Mycobacterium fortuitum, Mycobacterium marinum,        Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium        abscessus, Mycobacterium leprae, Mycobacterium smegmitis,        Mycobacterium africanum, Mycobacterium alvei, Mycobacterium        asiaticum, Mycobacterium aurum, Mycobacterium bohemicum,        Mycobacterium bovis, Mycobacterium branderi, Mycobacterium        brumae, Mycobacterium celatum, Mycobacterium chubense,        Mycobacterium confluentis, Mycobacterium conspicuum,        Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium        gadium, Mycobacterium gastri, Mycobacterium genavense,        Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium        haemophilum, Mycobacterium hassicum, Mycobacterium        intracellulare, Mycobacterium interjectum, Mycobacterium        heidelberense, Mycobacterium lentiflavum, Mycobacterium        malmoense, Mycobacterium microgenicum, Mycobacterium microti,        Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium        nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei,        Mycobacterium scrofulaceum, Mycobacterium shimoidei,        Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium        terse, Mycobacterium thermoresistabile, Mycobacterium triplex,        Mycobacterium triviale, Mycobacterium tusciae, Mycobacterium        ulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi and        Mycobacterium xenopi);    -   Haemophilus (e.g. Haemophilus influenzae, Haemophilus ducreyi,        Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus        haemolyticus and Haemophilus parahaemolyticus);    -   Actinobacillus (e.g. Actinobacillus actinomycetemcomitans,        Actinobacillus equuli, Actinobacillus hominis, Actinobacillus        lignieresii, Actinobacillus suis and Actinobacillus ureae);    -   Actinomyces (e.g. Actinomyces israelii);

Brucella (e.g. Brucella abortus, Brucella canis, Brucella melintensisand Brucella suis);

-   -   Campylobacter (e.g. Campylobacter jejuni, Campylobacter coli,        Campylobacter lari and Campylobacter fetus);    -   Listeria monocytogenes;    -   Vibrio (e.g. Vibrio cholerae and Vibrio parahaemolyticus, Vibrio        alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio        furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus        and Vibrio vulnificus);    -   Erysipelothrix rhusopathiae;    -   Corynebacteriaceae (e.g. Corynebacterium diphtheriae,        Corynebacterium jeikeum and Corynebacterium urealyticum);    -   Spirochaetaceae, such as Borrelia (e.g. Borrelia recurrentis,        Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii,        Borrelia bissettii, Borrelia garinii, Borrelia japonica,        Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia        valaisiana, Borrelia caucasica, Borrelia crocidurae, Borrelia        duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia        hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia        parkeri, Borrelia persica, Borrelia turicatae and Borrelia        venezuelensis) and Treponema (Treponema pallidum ssp. pallidum,        Treponema pallidum ssp. endemicum, Treponema pallidum ssp.        pertenue and Treponema carateum);    -   Pasteurella (e.g. Pasteurella aerogenes, Pasteurella bettyae,        Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum,        Pasteurella haemolytica, Pasteurella multocida multocida,        Pasteurella multocida gallicida, Pasteurella multocida septica,        Pasteurella pneumotropica and Pasteurella stomatis);    -   Bordetella (e.g. Bordetella bronchiseptica, Bordetella hinzii,        Bordetella holmseii, Bordetella parapertussis, Bordetella        pertussis and Bordetella trematum);    -   Nocardiaceae, such as Nocardia (e.g. Nocardia asteroides and        Nocardia brasiliensis);    -   Rickettsia (e.g. Ricksettsii or Coxiella burnetii);    -   Legionella (e.g. Legionalla anisa, Legionalla birminghamensis,        Legionalla bozemanii, Legionalla cincinnatiensis, Legionalla        dumoffii, Legionalla feeleii, Legionalla gormanii, Legionalla        hackeliae, Legionalla israelensis, Legionalla jordanis,        Legionalla lansingensis, Legionalla longbeachae, Legionalla        maceachernii, Legionalla micdadei, Legionalla oakridgensis,        Legionalla pneumophila, Legionalla sainthelensi, Legionalla        tucsonensis and Legionalla wadsworthii);    -   Moraxella catarrhalis;    -   Stenotrophomonas maltophilia;    -   Burkholderia cepacia;    -   Francisella tularensis;    -   Gardnerella (e.g. Gardneralla vaginalis and Gardneralla        mobiluncus);    -   Streptobacillus moniliformis;    -   Flavobacteriaceae, such as Capnocytophaga (e.g. Capnocytophaga        canimorsus, Capnocytophaga cynodegmi, Capnocytophaga gingivalis,        Capnocytophaga granulosa, Capnocytophaga haemolytica,        Capnocytophaga ochracea and Capnocytophaga sputigena);    -   Bartonella (Bartonella bacilliformis, Bartonella clarridgeiae,        Bartonella elizabethae, Bartonella henselae, Bartonella quintana        and Bartonella vinsonii arupensis);    -   Leptospira (e.g. Leptospira biflexa, Leptospira borgpetersenii,        Leptospira inadai, Leptospira interrogans, Leptospira        kirschneri, Leptospira noguchii, Leptospira santarosai and        Leptospira weilii);    -   Spirillium (e.g. Spirillum minus);    -   Baceteroides (e.g. Bacteroides caccae, Bacteroides capillosus,        Bacteroides coagulans, Bacteroides distasonis, Bacteroides        eggerthii, Bacteroides forsythus, Bacteroides fragilis,        Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis,        Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides        stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron,        Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides        vulgatus);    -   Prevotella (e.g. Prevotella bivia, Prevotella buccae, Prevotella        corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella        denticola, Prevotella disiens, Prevotella enoeca, Prevotella        heparinolytica, Prevotella intermedia, Prevotella loeschii,        Prevotella melaminogenica, Prevotella nigrescens, Prevotella        oxalis, Prevotella oris, Prevotella oulora, Prevotella tannerae,        Prevotella venoralis and Prevotella zoogleoformans);    -   Porphyromonas (e.g. Porphyromonas asaccharolytica, Porphyromonas        cangingivalis, Porphyromonas canons, Porphyromonas cansulci,        Porphyromonas catoniae, Porphyromonas circumdentaria,        Porphyromonas crevioricanis, Porphyromonas endodontalis,        Porphyromonas gingivalis, Porphyromonas gingivicanis,        Porphyromonas levii and Porphyromonas macacae);    -   Fusobacterium (e.g. F. gonadiaformans, F. mortiferum, F.        naviforme, F. necrogenes, F. necrophorum necrophorum, F.        necrophorum fundiliforme, F. nucleatum nucleatum, F. nucleatum        fusiforme, F. nucleatum polymorphum, F. nucleatum vincentii, F.        periodonticum, F. russii, F. ulcerans and F. varium);    -   Chlamydia (e.g. Chlamydia trachomatis);    -   Chlamydophila (e.g. Chlamydophila abortus (Chlamydia psittaci),        Chlamydophila pneumoniae (Chlamydia pneumoniae) and        Chlamydophila psittaci (Chlamydia psittaci));    -   Leuconostoc (e.g. Leuconostoc citreum, Leuconostoc cremoris,        Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc        mesenteroides and Leuconostoc pseudomesenteroides);    -   Gemella (e.g. Gemella bergeri, Gemella haemolysans, Gemella        morbillorum and Gemella sanguinis); and    -   Ureaplasma (e.g. Ureaplasma parvum and Ureaplasma urealyticum).

In one embodiment of the invention, the term “bacteria” includesreferences to any of the above classes or specific types of organisms,except for Shigella (e.g. Shigella flexneri) or Salmonella (e.g.Salmonella typhi).

When used herein, the terms “fungi” (and derivatives thereof, such as“fungal infection”) includes references to organisms (or infections dueto organisms) of the following classes and specific types:

-   -   Absidia (e.g. Absidia corymbifera);    -   Ajellomyces (e.g. Ajellomyces capsulatus and Ajellomyces        dermatitidis);    -   Arthroderma (e.g. Arthroderma benhamiae, Arthroderma fulvum,        Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae        and Arthroderma vanbreuseghemii);    -   Aspergillus (e.g. Aspergillus flavus, Aspergillus fumigatus and        Aspergillus niger);    -   Blastomyces (e.g. Blastomyces dermatitidis);    -   Candida (e.g. Candida albicans, Candida glabrata, Candida        guilliermondii, Candida krusei, Candida parapsilosis, Candida        tropicalis and Candida pelliculosa);    -   Cladophialophora (e.g. Cladophialophora carrionii);    -   Coccidioides (e.g. Coccidioides immitis);    -   Cryptococcus (e.g. Cryptococcus neoformans);    -   Cunninghamella (e.g. Cunninghamella sp.)    -   Epidermophyton (e.g. Epidermophyton floccosum);    -   Exophiala (e.g. Exophiala dermatitidis);    -   Filobasidiella (e.g. Filobasidiella neoformans);    -   Fonsecaea (e.g. Fonsecaea pedrosoi);    -   Fusarium (e.g. Fusarium solani);    -   Geotrichum (e.g. Geotrichum candidum);    -   Histoplasma (e.g. Histoplasma capsulatum);    -   Hortaea (e.g. Hortaea werneckii);    -   Issatschenkia (e.g. Issatschenkia orientalis);    -   Madurella (e.g. Madurella grisae);    -   Malassezia (e.g. Malassezia furfur, Malassezia globosa,        Malassezia obtusa, Malassezia pachydermatis, Malassezia        restricta, Malassezia slooffiae and Malassezia sympodialis);    -   Microsporum (e.g. Microsporum canis, Microsporum fulvum and        Microsporum gypseum);    -   Mucor (e.g. Mucor circinelloides);    -   Nectria (e.g. Nectria haematococca);    -   Paecilomyces (e.g. Paecilomyces variotii);    -   Paracoccidioides (e.g. Paracoccidioides brasiliensis);    -   Penicillium (e.g. Penicillium marneffei);    -   Pichia (e.g. Pichia anomala and Pichia guilliermondii);    -   Pneumocystis (e.g. Pneumocystis jiroveci (Pneumocystis        carinii));    -   Pseudallescheria (e.g. Pseudallescheria boydii);    -   Rhizopus (e.g. Rhizopus oryzae);    -   Rhodotorula (e.g. Rhodotorula rubra);    -   Scedosporium (e.g. Scedosporium apiospermum);    -   Schizophyllum (e.g. Schizophyllum commune);    -   Sporothrix (e.g. Sporothrix schenckii);    -   Trichophyton (e.g. Trichophyton mentagrophytes, Trichophyton        rubrum, Trichophyton verrucosum and Trichophyton violaceum); and    -   Trichosporon (e.g. Trichosporon asahii, Trichosporon cutaneum,        Trichosporon inkin and Trichosporon mucoides).

Thus, compounds of formula I, or combination products comprisingcompounds of formula I, may be used to kill any of the above-mentionedbacterial or fungal organisms (clinically latent or otherwise).

Particular bacteria that may be mentioned in this respect include:

-   -   Staphylococci, such as Staph. aureus (either        Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e.        MRSA)) and Staph. epidermidis;    -   Streptococci, such as Strept. agalactiae and Strept. pyogenes;    -   Bacillaceae, such as Bacillus anthracis;    -   Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g.        Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr.        mirabilis, Pr. rettgeri and Pr. vulgaris);    -   Haemophilis influenzae;    -   Enterococci, such as Enterococcus faecalis and Enterococcus        faecium; and    -   Mycobacteria, such as Mycobacterium tuberculosis.

Particular fungi that may also be mentioned in this respect includeAspergillus fumigatus, Candida albicans, Cryptococcus neoformans,Histoplasma capsulatum and Pneumocystis jiroveci.

Particular bacterial or fungal infections that may be mentioned inrelation to

-   (i) the use according to the fourth aspect of the invention,-   (ii) the method according to the sixth aspect of the invention and-   (iii) the above-described use and method involving the combination    product according to the seventh aspect of the invention (i.e.    use (iii) above or method (iv) above),    include infections with    -   Staph. aureus (either Methicillin-sensitive (i.e. MSSA) or        Methicillin-resistant (i.e. MRSA)) and Staph. epidermidis,    -   Streptococci, such as Strept. agalactiae and Strept. pyogenes,    -   Bacillaceae, such as Bacillus anthracis,    -   Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g.        Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr.        mirabilis, Pr. rettgeri and Pr. vulgaris),    -   Haemophilis influenzae,    -   Enterococci, such as Enterococcus faecalis and Enterococcus        faecium,    -   Mycobacteria, such as Mycobacterium tuberculosis or    -   fungi such as Aspergillus fumigatus, Candida albicans,        Cryptococcus neoformans, Histoplasma capsulatum and Pneumocystis        jiroveci.

In this respect, particular conditions that the compounds of formula I,or combination products comprising compounds of formula I, can be usedto treat include tuberculosis (e.g. pulmonary tuberculosis,non-pulmonary tuberculosis (such as tuberculosis lymph glands,genito-urinary tuberculosis, tuberculosis of bone and joints,tuberculosis meningitis) and miliary tuberculosis), anthrax, abscesses,acne vulgaris, actinomycosis, bacilliary dysentry, bacterialconjunctivitis, bacterial keratitis, botulism, Buruli ulcer, bone andjoint infections, bronchitis (acute or chronic), brucellosis, burnwounds, cat scratch fever, cellulitis, chancroid, cholangitis,cholecystitis, cutaneous diphtheria, cystic fibrosis, cystitis, diffusepanbronchiolitis, diphtheria, dental caries, diseases of the upperrespiratory tract, empymea, endocarditis, endometritis, enteric fever,enteritis, epididymitis, epiglottitis, erysipclas, erysipeloid,erythrasma, eye infections, furuncles, Gardnerella vaginitis,gastrointestinal infections (gastroenteritis), genital infections,gingivitis, gonorrhoea, granuloma inguinale, Haverhill fever, infectedburns, infections following dental operations, infections in the oralregion, infections associated with prostheses, intraabdominal abscesses,Legionnaire's disease, leprosy, leptospirosis, listeriosis, liverabscesses, Lyme disease, lymphogranuloma venerium, mastitis,mastoiditis, meningitis and infections of the nervous system, mycetoma,nocardiosis (e.g. Madura foot), non-specific urethritis, opthalmia (e.g.opthalmia neonatorum), osteomyelitis, otitis (e.g. otitis externa andotitis media), orchitis, pancreatitis, paronychia, pelveoperitonitis,peritonitis, peritonitis with appendicitis, pharyngitis, phlegmons,pinta, plague, pleural effusion, pneumonia, postoperative woundinfections, postoperative gas gangrene, prostatitis, pseudo-membranouscolitis, psittacosis, pulmonary emphysema, pyelonephritis, pyoderma(e.g. impetigo), Q fever, rat-bite fever, reticulosis, Ritter's disease,salmonellosis, salpingitis, septic arthritis, septic infections,septicameia, sinusitis, skin infections (e.g. skin granulomas),syphilis, systemic infections, tonsillitis, toxic shock syndrome,trachoma, tularaemia, typhoid, typhus (e.g. epidemic typhus, murinetyphus, scrub typhus and spotted fever), urethritis, wound infections,yaws, aspergillosis, candidiasis (e.g. oropharyngeal candidiasis,vaginal candidiasis or balanitis), cryptococcosis, favus,histoplasmosis, intertrigo, mucormycosis, tinea (e.g. tinea corporis,tinea capitis, tinea cruris, tinea pedis and tinea unguium),onychomycosis, pityriasis versicolor, ringworm and sporotrichosis.

Further conditions that may be mentioned in this respect includeinfections with MSSA, MRSA, Staph. epidermidis, Strept. agalactiae,Strept. pyogenes, Escherichia coli, Klebs. pneumoniae, Klebs. oxytoca,Pr. mirabilis, Pr. rettgeri, Pr. vulgaris, Haemophilis influenzae,Enterococcus faecalis or Enterococcus faecium.

Specific compounds of formula I that may be mentioned in relation to theabove-described aspects of the invention include the followingcompounds:

-   (a)    6,8-dimethoxy-1-(4-iso-propylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (b)    6-methoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (c)    6-methoxy-1-(4-iso-propylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (d)    6,8-dimethoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (e)    4-methyl-8-phenoxy-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (f)    1-(4-iso-propylphenyl)-6-phenoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;    and-   (g)    4,6-dimethyl-1-(4-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    as well as, particularly, the compounds of Examples 1 to 8 below.

The use of certain compounds of formula I in medicine, includingcompounds of formula I (and Ia), as hereinbefore defined, is, to theknowledge of the inventors, novel.

For the avoidance of doubt, references herein to compounds of formula Iinclude references to all embodiments described above in relation tocompounds of formulae I and Ia.

In this respect, a further aspect of the invention provides a compoundof formula Ib for use in medicine, wherein compounds of formula Ib takethe same definition as compounds of formula I, as hereinbefore defined,except that the compound is not:

-   (a) of the following formula

-   -   in which    -   (i) R^(A) represents methyl, benzyl or CH₂CH₂N(C₁₋₂ alkyl)₂,        R^(B) represents H,        -   R^(C) represents H or methyl and        -   R^(D) represents H or one or two substituents selected from            Cl, OH,        -   C₁₋₂ alkoxy and C(O)N(H)CH₃,    -   (ii) R^(A) represents CH(C₂H₅)₂ or CH(C₂H₅)(CH₂OCH₃),        -   R^(B) represents H,        -   R^(C) represents methyl or 2,4,6-trimethylphenyl and        -   R^(D) represents a single substituent selected from            2,4,6-trimethylphenyl and iodo,    -   (iii) R^(A) represents benzyl, 1-phenylethyl or phenyl, which        latter group is substituted at the 2-position by methyl or        methoxy and is optionally further substituted at the 4-position        by fluoro, OH, methyl, methoxy or benzyloxy, or at the        6-position by methyl,        -   R^(B) represents H, C₁₋₃ alkyl (e.g. methyl, ethyl or            iso-propyl) or C₁₋₂ alkyl terminated by OH,        -   R^(C) represents H, methyl or hydroxymethyl and        -   R^(D) represents H or a single substituent (e.g. at the            6-position) selected from F, OH, methyl, methoxy,            trifluoromethoxy, OCH₂CH₂OH or OCH₂CF₃,    -   (iv) R^(A) represents methyl, 2-hydroxyethyl or phenyl, which        latter group is optionally singly substituted in the 2-position        by chloro or in the 4-position by methyl or methoxy,        -   R^(B) represents H,        -   R^(C) represents methyl and        -   R^(D) represents H or a single substituent (e.g. at the            6-position) selected from OH and methoxy,    -   (v) R^(A) represents phenyl substituted by a single OH or        methoxy group,        -   R^(B) represents H,        -   R^(C) represents methyl and        -   R^(D) represents H or    -   (vi) R^(A) represents H or phenyl optionally substituted by a        single substituent (e.g. at the 4-position) selected from        methyl, chloro or fluoro, or by a single trifluoromethyl        substituent (e.g. at the 3-position),        -   R^(B) represents H,        -   R^(C) represents methyl and        -   R^(D) represents a single chloro or fluoro substituent (e.g.            at the 8-position) or two substituents (e.g. at the 6- and            8- or 6- and 9-positions) which are both either chloro or            methoxy; or

-   (b) of the following formula

-   -   in which    -   (i) R^(A1) represents 2-ethoxyethyl or CH(R^(alk1))(R^(alk2)),        wherein R^(alk1) and        -   R^(alk2) independently represent ethyl, n-propyl or            methoxymethyl,        -   R^(B1) and R^(B2) both represent H,        -   R^(C1) represents methyl or 2,4,6-trimethylphenyl and        -   R^(D1) represents a single substituent (e.g. at the 6- or            7-position) that is selected from iodo, methyl, aryl or            Het⁶, wherein aryl and Het⁶ are as hereinbefore defined, or            R^(D1) represents a methyl substituent at the 6-position and            a mesityl substituent at the 7-position,    -   (ii) R^(A1) represents C₁₋₂ alkyl, 1-phenylethyl or phenyl,        which latter group is substituted at the 2-position by methyl or        methoxy and is    -   optionally further substituted at the 4-position by F, OH,        methoxy, acetoxy or benzyloxy,    -   R^(B1) represents H,    -   R^(B2) represents H, C₁₋₃ alkyl or C₁₋₂ alkyl terminated by OH,    -   R^(C1) represents H or methyl and    -   R^(D1) represents a single substituent (e.g. at the 6-position)        that is selected from Cl, OH, methoxy, trifluoromethoxy,        OCH₂CH₂OH or OCH₂CF₃,    -   (iii) R^(A1) represents methyl, n-butyl, benzyl or phenyl, which        latter group is substituted at the 2-position by methyl and is        optionally further substituted at the 4-position by F, methoxy,        OC(O)O-1-butyl or OC(O)-i-butyl,        -   R^(B1) represents H, methyl, hydroxymethyl, n-propyl or            phenyl,        -   R^(B2) represents H, C₁₋₃ alkyl, hydroxymethyl or phenyl,        -   R^(C1) represents H or methyl and        -   R^(D1) represents a single substituent (e.g. at the            6-position) that is selected from Cl and methoxy,    -   (iv) R^(A1) represents phenyl, which group is optionally        substituted by F or methoxy,        -   R^(B1), R^(B2) and R^(C1) all represent trifluoromethyl and        -   R^(D1) represents H or a single substituent that is selected            from F and methoxy,    -   (v) R^(A1), R^(B1), R^(B2) and R^(C1) all represent methyl and        -   R^(D1) represents one or two substituents selected from Cl,            methyl and methoxy,    -   (vi) R^(A1) represents methyl, ethyl, 2-ethoxyethyl,        2-isopropoxyethyl, 3-methoxypropyl, n-butyl or phenyl,        -   R^(B1) represents methyl, hydroxymethyl or n-propyl,        -   R^(B2) represents H or phenyl,        -   R^(C1) represents H or methyl and        -   R^(D1) represents a single substituent (e.g. at the            6-position) that is selected from Cl, methoxy and            2,4,6-trimethylphenyl or    -   (vii) R^(A1) represents phenyl,        -   R^(B1) and R^(B2) both represent H,        -   R^(C1) represents methyl and        -   R^(D1) represents H or a single methoxy substituent (e.g. at            the 8-position).

The use of compounds of formula Ib in medicine includes their use aspharmaceuticals. The invention therefore further provides for the use ofa compound of formula Ib as a pharmaceutical.

Specific compounds of formula Ib that may be mentioned include thefollowing compounds:

-   (a)    6,8-dimethoxy-1-(4-iso-propylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (b)    6-methoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (c)    6-methoxy-1-(4-iso-propylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (d)    6,8-dimethoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (e)    4-methyl-8-phenoxy-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (f)    1-(4-iso-propylphenyl)-6-phenoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;    and-   (g)    4,6-dimethyl-1-(4-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    as well as, particularly, the compounds of Examples 1 to 8 below.

Certain compounds of formula I, Ia and Ib are to the knowledge of theinventors, novel per se. Thus, in a still further aspect of theinvention, there is provided a compound of formula Ic, wherein compoundsof formula Ic take the same definition as compounds of formula Ib, ashereinbefore defined, except that the compound is not:

-   (a) of the following formula

-   -   in which    -   (i) R^(A) represents 2-(dimethylamino)ethyl,        -   R^(B) represents H,        -   R^(C) represents methyl and        -   R^(D) represents one or two substituents selected from Cl,            OH and methoxy,    -   (ii) R^(A) represents phenyl substituted by one or two        substituents consisting of an ethyl group at the 4-position or        one or two methoxy groups at the 2- and/or 4-positions,        -   R^(B) represents H,        -   R^(C) represents methyl and        -   R^(D) represents one or two substituents, at the 6- and/or            8-positions, selected from trifluoromethyl and methoxy or    -   (iii) R^(A) represents methyl or phenyl, which latter group is        optionally substituted by a single substituent selected from Cl,        F, methyl, trifluoromethyl and methoxy, or by two methyl groups        (e.g. at the 2- and 6-positions),        -   R^(B) represents H,        -   R^(C) represents H or methyl and        -   R^(D) represents H or one or two substituents selected from            Cl, F, methyl and methoxy; or

-   (b)    -   (i)        7,9-dibromo-6-hydroxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (ii)        6-methoxy-4,5-dimethyl-1-(2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinium        iodide;    -   (iii) 1-ethyl-5-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinium        hexafluorophosphate;    -   (iv)        6,8-dimethoxy-1-(4-iso-propylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (v)        6-methoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (vi)        6-methoxy-1-(4-iso-propylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (vii)        6,8-dimethoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (viii)        6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (ix)        6,9-dimethoxy-1,2,3,4-tetramethyl-1H-pyrrolo[3,2-c]quinoline,    -   (x)        6,9-dimethoxy-1,2,3,4,8-pentamethyl-1H-pyrrolo[3,2-c]quinoline,    -   (xi)        2,3-difluoro-1-phenyl-2,3,4-tris(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline        or    -   (xii)        6,9-dimethoxy-2,3,4,8-tetramethyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline.

Compounds of formula Ic that may be mentioned include those that either(a) are, or (b) are not:

-   -   (xi)        1-(4-methoxyphenyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (xii)        4-methyl-8-phenoxy-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (xiii)        1-(4-iso-propylphenyl)-8-phenoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (xiv)        1-(4-iso-propylphenyl)-6-phenoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,    -   (xv)        6-phenoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,        or    -   (xvi)        6-phenoxy-1-(4-trifluoromethoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline.

Particular compounds of formulae Ib and Ic that may be mentioned includethose in which:

-   (a) R¹ is other than H;-   (b) R² is other than H; and-   (c) R¹ and R² are both other than H.

Compounds of formula Ic that may be mentioned include those in which:

-   (1) X represents —CH₂—CH₂—;-   (2) R¹ represents    -   (a) C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl or C₄₋₁₂        cycloalkenyl, which latter four groups are optionally        substituted by one or more substituents selected from halo,        nitro, CN, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₃₋₈        cycloalkyl (which latter three groups are optionally substituted        by one or more substituents selected from OH, ═O, halo, C₁₋₄        alkyl and C₁₋₄ alkoxy), OR^(5a), S(O)_(p)R^(5b),        S(O)₂N(R^(5c))(R^(5d)), N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)),        B³—C(O)—B⁴—R^(5i), aryl and Het³, and which C₃₋₁₂ cycloalkyl or        C₄₋₁₂ cycloalkenyl groups may additionally be substituted by ═O,    -   (b) aryl substituted as defined above in respect of aryl groups,        except that the substituents include at least one OR^(10a) group        in which R^(10a) is other than H or C₁₋₁₂ alkyl (which latter        group is optionally substituted as defined above in respect of        R^(10a)) or    -   (c) Het²;-   (3) R¹ represents    -   (a) C₃₋₁₂ cycloalkyl, which latter groups is optionally fused to        a benzene ring and is optionally substituted by one or more        substituents selected from halo, nitro, CN, C₁₋₆ alkyl, C₁₋₆        alkenyl, C₁₋₆ alkynyl, C₃₋₈ cycloalkyl (which latter three        groups are optionally substituted by one or more substituents        selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₄ alkoxy), OR^(5a),        ═O, S(O)_(p)R^(5b), S(O)₂N(R^(5e))(R^(5d)), N(R^(5e))        S(O)₂R^(5f), N(R⁵)(R^(5h)), B³—C(O)—B⁴—R^(5i), aryl and Het³,    -   (b) phenyl substituted as defined above in respect of aryl        groups, except that the substituents include at least one        OR^(10a) group in which R^(10a) is phenyl (which latter group is        optionally substituted by one or more substituents selected from        OH, halo, methyl and methoxy) or    -   (c) Het²;-   (4) R¹ represents    -   (a) C₄₋₅ cycloalkyl fused to a benzene ring and optionally        substituted by one or more substituents selected from halo, C₁₋₄        alkyl, OH and C₁₋₄ alkoxy or    -   (b) phenyl substituted as defined above in respect of aryl        groups, except that the substituents include at least one        OR^(10a) group in which R^(10a) is phenyl (which latter group is        optionally substituted by one or more substituents selected from        OH, halo, methyl and methoxy);        (5) R³ represents one to four substituents on the fused benzene        ring, as defined above in respect of R³, except that the        substituents include at least one OR^(7a) in which R^(7a) is        other than H or C₁₋₁₀ alkyl (which latter group is optionally        substituted as defined above in respect of R^(7a));-   (6) R³ represents one to four (e.g. one or two) substituents on the    fused benzene ring, as defined above in respect of R³, except that    the substituents include at least one OR^(7a) in which R^(7a) is    phenyl (which latter group is optionally substituted by one or more    substituents selected from OH, halo, methyl and methoxy);-   (7) R² represents unsubstituted C₁₋₃ alkyl, such as methyl.

Further, specific compounds of formula Ic that may be mentioned includecompounds of Examples 1 to 8 below. Still further compounds of formulaIc that may be mentioned include compounds of Examples 1 to 8 below,except for the following compounds:

-   (1)    1-(4-methoxyphenyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (2)    4-methyl-8-phenoxy-1-(4-iso-propylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;    and-   (3)    6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline.

When used herein, the term “compounds of Examples 1 to 8 below” refersto the title compounds of those examples, i.e.:

-   (1)    6,8-dimethoxy-4-methyl-1-(3-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (2)    6,8-dimethoxy-4-methyl-1-(2-phenoxyethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (3)    1-cyclopropyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (4)    8-methoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (5)    {2-[4-(8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-1-yl)-phenyoxy]ethyl}dimethylamine;-   (6)    8-methoxy-4-methyl-1-[4-(pyridin-3-yloxy)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (7)    4-methyl-8-phenoxy-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (8)    1-benzyl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-   (9)    1-(indan-2-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-   (10)    4-methyl-6-phenoxy-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (11)    1-benzyl-4-methyl-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (12)    1-(indan-2-yl)-4-methyl-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (13)    4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (14)    8-methoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinolin-6-ol;-   (15)    1-(1-benzyl-piperidin-4-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (16)    1-(indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (17)    1-(benzodioxan-2-ylmethyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (18)    4-methyl-8-phenoxy-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (19)    1-cyclohexyl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (20)    8-ethoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (21)    1-(4-methoxyphenyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (22)    4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (23)    4-methyl-1-(2-methylphenyl)methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (24)    4-methyl-8-phenoxy-1-(4-iso-propylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (25)    4-methyl-8-phenoxy-1-(1-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (26)    8-methoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (27)    6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (28)    6,8-dimethoxy-1-(3-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (29)    6,8-dimethoxy-1-(3-hydroxy-5-methylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (30)    8-methoxy-1-(4-methoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (31)    8-trifluoromethoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (32)    6,8-dimethoxy-4-methyl-1-[4-(pyridin-3-yloxy)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (33)    1-benzyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (34)    6,8-dimethoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (35)    4-methyl-1-(2-phenylethyl)-8-trifluoromethoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (36)    6,8-dimethoxy-1-(indan-1-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (37)    6,8-dimethoxy-4-methyl-1-[(6-phenoxy)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (38)    6,8-dimethoxy-1-[(6-methoxy)pyridin-3-yl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (39)    1-(benzodioxol-5-ylmethyl)-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (40)    6,8-dimethoxy-4-methyl-1-(3-methylbutyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (41)    1-cyclopropylmethyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (42)    4-methyl-8-(morpholin-4-yl)-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (43)    8-methoxy-4-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (44)    4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (45)    4,6-dimethyl-1-(2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (46)    4,6-dimethyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (47)    4-methyl-8-(piperidin-1-yl)-1-[4-(piperidin-1-yl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (48)    4-methyl-8-(piperidin-1-yl)-1-(3-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (49)    1-{4-[2-(N,N-dimethylamino)ethoxy]phenyl}-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (50)    1-[4-(4-fluorophenoxy)phenyl]-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (51)    1-(benzodioxan-2-ylmethyl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (52)    1-cyclohexyl-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (53)    8-methoxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (54)    4-methyl-8-phenoxy-1-[4-(3-pyridyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (55)    4-methyl-8-phenoxy-1-[2-(3-pyridyl)ethyl]-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (56)    4-methyl-8-phenoxy-1-(2-pyridylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (57)    4-methyl-1-(5-methylpyrazin-2-ylmethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (58)    8-chloro-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (59) methyl    4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylate;-   (60)    4-methyl-8-(morpholin-1-yl)-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (61)    ethyl[4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-yl]acetate;-   (62)    1-[3-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-1-yl)propyl]-pyrrolidin-2-one;-   (63)    4-methyl-8-phenoxy-1-[2-(2-pyridyl)ethyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (64) ethyl    3-(8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)propionate;-   (65) ethyl    4-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)butanoate;-   (66) methyl    4-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)butanoate;-   (67) ethyl    (4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)acetate;-   (68)    4-methyl-1-(1-methylpiperidin-4-yl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (69)    1-(1-benzylpyrrolidin-3-yl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (70) methyl    3-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)propionate;-   (71)    1-((S)-indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (72)    1-((R)-indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (73)    1-(3-methoxypropyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (74)    4-methyl-8-phenoxy-1-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (75)    1-[2-(4-chlorophenyl)ethyl]-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (76)    1-[2-(4-methoxyphenyl)ethyl]-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (77)    4-methyl-8-phenoxy-1-(2-phenylpropyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (78)    8-cyano-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (79)    8-hydroxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (80)    8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (81)    6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methylpyrrolo[3,2-c]quinoline;-   (82)    8-methoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;-   (83)    4-methyl-8-phenylamino-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;-   (84)    [4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[2,3-c]quinoline-8-oyl]-piperidine,    and pharmaceutically-acceptable salts and/or solvates thereof.

As well as having activity against fungi and bacteria, compounds offormulae Ib and Ic may also have activity against other organisms, suchas protozoa. Therefore, according to further aspects of the invention,there is provided:

-   (i) the use of a compound of formula Ib or Ic, as hereinbefore    defined, for the preparation of a medicament for the treatment of a    protozoal disease;-   (ii) a method of treating a protozoal disease in a mammal, the    method comprising administering to said mammal an effective amount    of a compound of formula Ib or Ic, as hereinbefore defined;-   (iii) use (e.g. ex vivo use) of a compound of formula Ib or Ic for    killing protozoa.

When used herein, the terms “protozoa” (and derivatives thereof, such as“protozoal disease”) includes references to organisms (or infections dueto organisms) of the following classes and specific types:

-   -   Leishmania (e.g. Leishmania donovanii);    -   Plasmodium spp.;    -   Trypanosoma spp.;    -   Giardia lamblia;    -   coccidia (e.g. Cryptosporidium parvum, Isospora belli);    -   Toxoplasma (e.g. Toxoplasma gondii);    -   Balantidium coli;    -   amoeba (e.g. Entamoeba, such as Entamoeba histolytica, Entamoeba        coli, Entamoeba hartmanni and Entamoeba polecki); and    -   Microsporidia (e.g. Enterocylozoon bieneusi, Encephalitozoon        hellem, Encephalitozoon cuniculi and Septata intestinalis).

Particular conditions that the compounds of formula Ib or Ic can be usedto treat include Leishmaniasis, malaria, trypanosomiasis, toxoplasmosis,giardiasis, balantidiasis, amoebiasis (amoebic dysentery),cryptosporidiosis, isosporiasis and microsporidiosis.

In addition, compounds of formula I and Ia may be employed in the use ormethod at (i) and (ii) above when the protozoal disease is other thanmalaria or amoebiasis. Further, compounds of formula I and Ia may beemployed in the use at (iii) above when the protozoa are other thanPlasmodium spp. or amoeba.

Compounds of formula I (including compounds of formulae Ia, Ib and Ic)may be prepared in accordance with techniques known to those skilled inthe art, for example as described hereinafter.

Thus, according to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I (e.g. a compoundof formula Ic), which comprises:

(a) for compounds of formula I in which X represents—C(R^(8a))(R^(8b))—C(R^(8c))(R^(8d))—, reaction of a compound of formulaII,

wherein L¹ and L² independently represent a suitable leaving group (e.g.halo) and R², R³, R^(8a), R^(8b), R^(8c) and R^(8d) are as hereinbeforedefined, with a compound of formula III,

R¹—NH₂  III

wherein R¹ is as hereinbefore defined, for example under conditionsknown to those skilled in the art (e.g. by reaction at elevatedtemperature (such as 70 to 225° C.) and/or pressure (i.e. above 1atmosphere) in the presence of a suitable organic solvent, such as aC₁₋₄ alcohol (e.g. ethanol or n-butanol) (for example, the reaction maybe performed by reaction of the compound of formula II with between 1and 3 equivalents (e.g. from 1.5 to 2 equivalents) of the compound offormula III at elevated temperature (e.g. above 120° C., such as from150 to 200° C. or, particularly, from 175 to 185° C. (e.g. 180° C.)),wherein the reaction mixture is optionally heated by use of microwaves,in the presence of a suitable high-boiling solvent (e.g. an alkyleneglycol, such as ethylene glycol) or, when the compound of formula III isliquid at the reaction temperature, in the presence of excess compoundof formula III); or

(b) for compounds of formula I in which X represents—C(R^(8e))═C(R^(8f))—, dehydrogenation of a corresponding compound offormula I in which X represents —C(H)(R^(8a))—C(H)(R^(8c))—, for exampleunder conditions known to those skilled in the art (such as reaction atelevated temperature (e.g. from 70 to 225° C.) in the presence of a(de)hydrogenation catalyst (e.g. palladium supported on carbon) and asuitable, reaction-inert solvent (e.g. diphenylether)).

In the formation of compounds of formula I in which X represents—C(R^(8a))(R^(8b))—C(R^(8c))(R^(8d))— (e.g. as outlined at (a) above),elimination of extraneous oxidants (e.g. atmospheric oxygen), may beutilised in order to minimise the formation of corresponding compoundsof formula I in which X represents —C(R^(8e))═C(R^(8f))—. This may beeffected, for example, by degassing reaction solvents and/or reagents,or by use of an antioxidant (e.g. at a low level, such as 0.5 mol. %)such as butylated hydroxytoluene (“BHT”).

Compounds of formula II in which L¹ and L² both represent halo may beprepared according to methods known to those skilled in the art, forexample by reaction of a corresponding compound of formula IV,

wherein R², R³, R^(8a), R^(8b), R^(8c) and R^(8d) are as hereinbeforedefined, with a combined dehydrating/halogenating agent (e.g. P(O)Cl₃),for example under conditions know to those skilled in the art (e.g. atelevated temperature, optionally in the presence of a suitable organicsolvent). For example, the reaction may be performed by reaction atelevated temperature (e.g. from 75 to 120° C., such as from 90 to 100°C.) of the compound of formula IV with from 1 to 5 (e.g. 2) equivalentsof P(O)Cl₃, optionally (and preferably) in the presence of a suitablesolvent (e.g. acetonitrile or, particularly, toluene).

Compounds of formula IV may be prepared by reaction of a correspondingcompound of formula V,

wherein R³ is as hereinbefore defined, with a compound of formula VI,

wherein R², R³, R^(8a), R^(8b), R^(8c) and R^(8d) are as hereinbeforedefined, for example under conditions know to those skilled in the art(e.g. at elevated temperature, such as from 100 to 180° C.). Forexample, the reaction may be performed by reaction at elevatedtemperature (e.g. from 75 to 120° C., such as from 100 to 118° C.) ofthe compound of formula V with from 1 to 1.5 equivalents (e.g. 1 or 1.1equivalents) of the compound of formula VI in the presence of a suitablesolvent (e.g. a high-boiling, water-immiscible hydrocarbon, such astoluene) and optionally in the presence of a suitable catalyst (e.g. anacid, such as acetic acid or, particularly, an acidic polymer resin (ionexchange resin), such as a polysulfonated polymer of styrene orcopolymer of styrene and divinylbenzene (e.g. Amberlyst 15)). In thisinstance, the reaction may be performed in the presence of a dehydratingagent (such as molecular sieves) or in such a way that water generatedby the condensation reaction is removed whilst the reaction is inprogress (e.g. by use of a water-immiscible solvent such as toluene anda Dean-Stark apparatus, as known to those skilled in the art).

Compounds of formulae III, V and VI are either commercially available,are known in the literature, or may be obtained by analogy with theprocesses described herein, or by conventional synthetic procedures, inaccordance with standard techniques, from readily available startingmaterials using appropriate reagents and reaction conditions.

Substituents on alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryland heterocyclic groups in compounds of formulae I, II, III, IV, V andVI may be introduced and/or interconverted using techniques well knownto those skilled in the art by way of standard functional groupsinterconversions, in accordance with standard techniques, from readilyavailable starting materials using appropriate reagents and reactionconditions. For example, hydroxy may be converted to alkoxy, phenyl maybe halogenated to give halophenyl, halo may be displaced by cyano, etc.

Compounds of formula I may be isolated from their reaction mixturesusing conventional techniques. For example, compounds of formula I maybe isolated by conversion to an acid (e.g. hydrochloric acid) salt (e.g.by way of addition of acid to the crude product) and thenrecrystallisation of the salt from a suitable solvent (e.g. methanol or,particularly, ethanol). Alternatively, the salt can simply be washedwith or slurried in the presence such a suitable solvent in order toisolate the pure acid salt of the compound of formula I.

In accordance with the present invention, pharmaceutically acceptablederivatives of compounds of formula I also include “protected”derivatives, and/or compounds that act as prodrugs, of compounds offormula I.

Compounds of formula I may exhibit tautomerism. All tautomeric forms andmixtures thereof are included within the scope of the invention.

Compounds of formula I may also contain one or more asymmetric carbonatoms and may therefore exhibit optical and/or diastereoisomerism.Diastereoisomers may be separated using conventional techniques, e.g.chromatography. The various stereoisomers may be isolated by separationof a racemic or other mixture of the compounds using conventional, e.g.HPLC techniques. Alternatively the desired optical isomers may be madeby reaction of the appropriate optically active starting materials underconditions which will not cause racemisation or epimerisation, or byderivatisation, for example with a homochiral acid followed byseparation of the diastereomeric derivatives by conventional means (e.g.HPLC, chromatography over silica). All stereoisomers are included withinthe scope of the invention.

It will be appreciated by those skilled in the art that in the processesdescribed above and hereinafter the functional groups of intermediatecompounds may need to be protected by protecting groups.

Functional groups that it is desirable to protect include hydroxy, aminoand carboxylic acid. Suitable protecting groups for hydroxy includeoptionally substituted and/or unsaturated alkyl groups (e.g. methyl,allyl, benzyl or tert-butyl), trialkylsilyl or diarylalkylsilyl groups(e.g. t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) andtetrahydropyranyl. Suitable protecting groups for carboxylic acidinclude C₁₋₆ alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after coupling, or before or after any other reaction in theabove-mentioned schemes.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter.

Persons skilled in the art will appreciate that, in order to obtaincompounds of formula I in an alternative, and, on some occasions, moreconvenient, manner, the individual process steps mentioned hereinbeforemay be performed in a different order, and/or the individual reactionsmay be performed at a different stage in the overall route (i.e.substituents may be added to and/or chemical transformations performedupon, different intermediates to those mentioned hereinbefore inconjunction with a particular reaction). This may negate, or rendernecessary, the need for protecting groups.

The type of chemistry involved will dictate the need, and type, ofprotecting groups as well as the sequence for accomplishing thesynthesis.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Protected derivatives of compounds of formula I may be convertedchemically to compounds of the invention using standard deprotectiontechniques (e.g. hydrogenation). The skilled person will also appreciatethat certain compounds of formula I may also be referred to as being“protected derivatives” of other compounds of formula I.

Those skilled in the art will also appreciate that certain compounds offormula I will be useful as intermediates in the synthesis of certainother compounds of formula I.

When used in the above-described method of treatment, the compounds offormula Ib and Ic may be formulated for administration to a patient. Inthis respect, according to a still further aspect of the invention thereis provided a pharmaceutical formulation including a compound of formulaIb or Ic, in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier.

The above-mentioned medicaments, (components of) combination productsand pharmaceutical formulations may be prepared according to methodsknown to those skilled in the art, for example by mixing the compoundsof formulae I, Ia, Ib or Ic with excipient or excipients.

When formulated with excipients, the compounds of formulae I, Ia, Ib orIc may be present in the above-mentioned medicaments, (components of)combination products and pharmaceutical formulations in a concentrationfrom 0.1 to 99.5% (such as from 0.5 to 95%) by weight of the totalmixture.

When administered to patients by way of any of the above-mentionedmedicaments, (components of) combination products and pharmaceuticalformulations, compounds of formulae I, Ia, Ib or Ic will normally beadministered orally, by any parenteral route or via inhalation.

In the case of animals, compounds of formulae I, Ia, Ib or Ic can alsobe administered by incorporation of the compound of formulae I, Ia, Ibor Ic into feed or drinking water.

Preferred route of administration of compounds of the invention areoral.

Suitable daily doses of the compounds of the invention in prophylacticand/or therapeutic treatment of mammals (e.g. humans) include, forexample, 0.001-100 mg/kg body weight at peroral administration and0.001-50 mg/kg body weight at parenteral administration.

In a particular embodiment of the invention, compounds of formulae I,Ia, Ib or Ic are administered topically. Thus, according to theinvention there is provided:

-   (I) a topical pharmaceutical composition comprising a compounds of    formula I, Ia, Ib or Ic in admixture with a pharmaceutically    acceptable adjuvant, diluent or carrier;-   (II) a combination product for topical administration comprising    -   (A) a compound of formula I, as hereinbefore defined, and    -   (B) a conventional antibiotic agent, as hereinbefore defined,    -   wherein each of components (A) and (B) is formulated in        admixture with a pharmaceutically-acceptable adjuvant, diluent        or carrier.

In relation to (II) above, the combination product provides for theadministration of component (A) in conjunction with component (B), andmay thus be presented either as separate topical formulations, whereinat least one of those formulations comprises component (A) and at leastone comprises component (B), or may be presented (i.e. formulated) as acombined topical preparation (i.e. presented as a single topicalformulation including component (A) and component (B)).

Topical compositions, which are useful for treating disorders of theskin or of membranes accessible by digitation (such as membrane of themouth, vagina, cervix, anus and rectum), include creams, ointments,lotions, sprays, gels and sterile aqueous solutions or suspensions. Assuch, topical compositions include those in which the activeingredient(s) is (are) dissolved or dispersed in a dermatologicalvehicle known in the art (e.g. aqueous or non-aqueous gels, ointments,water-in-oil or oil-in-water emulsions). Constituents of such vehiclesmay comprise water, aqueous buffer solutions, non-aqueous solvents (suchas ethanol, isopropanol, benzyl alcohol, 2-(2-ethoxyethoxy)ethanol,propylene glycol, propylene glycol monolaurate, glycofurol or glycerol),oils (e.g. a mineral oil such as a liquid paraffin, natural or synthetictriglycerides such as Miglyol™, or silicone oils such as dimethicone).Depending, inter alia, upon the nature of the formulation as well as itsintended use and site of application, the dermatological vehicleemployed may contain one or more components selected from the followinglist:

-   -   a solubilising agent or solvent (e.g. a β-cyclodextrin, such as        hydroxypropyl β-cyclodextrin, or an alcohol or polyol such as        ethanol, propylene glycol or glycerol);    -   a thickening agent (e.g. hydroxyethylcellulose,        hydroxypropylcellulose, carboxymethylcellulose or carbomer);    -   a gelling agent (e.g. a polyoxyethylene-polyoxypropylene        copolymer);    -   a preservative (e.g. benzyl alcohol, benzalkonium chloride,        chlorhexidine, chlorbutol, a benzoate, potassium sorbate or EDTA        or salt thereof); and    -   pH buffering agent(s) (such as a mixture of dihydrogen phosphate        and hydrogen phosphate salts, or a mixture of citric acid and a        hydrogen phosphate salt).

The amount of compound of formulae I, Ia, Ib or Ic used in topicalcompositions or combination products will depend, inter alia, upon theparticular nature of the composition or combination product, as well asits intended use. In any event, those skilled in the art will be able todetermine, by routine and non-inventive methods, amounts of compound offormulae I, Ia, Ib or Ic that can be employed. Typically, however, thecompound of formulae I, Ia, Ib or Ic will be present in the topicalcomposition or combination product at from 0.01 to 25% by weight (e.g.from 0.1 to 10% by weight, such as from 0.1 to 5% by weight or,particularly, from 0.5 to 3% (e.g. 2%) by weight) of the composition orproduct.

Methods of producing topical pharmaceutical compositions such as creams,ointments, lotions, sprays and sterile aqueous solutions or suspensionsare well known in the art. Suitable methods of preparing topicalpharmaceutical compositions are described, for example in WO 95/10999,U.S. Pat. No. 6,974,585, WO 2006/048747, as well as in documents citedin any of these references.

Topical pharmaceutical compositions and combination products accordingto the present invention may be used to treat a variety of skin ormembrane disorders, such as infections of the skin or membranes (e.g.e.g. infections of nasal membranes, axilla, groin, perineum, rectum,dermatitic skin, skin ulcers, and sites of insertion of medicalequipment such as i.v. needles, catheters and tracheostomy or feedingtubes) with any of the bacteria, fungi described hereinbefore, (e.g. anyof the Staphylococci, Streptococci, Mycobacteria or Pseudomonasorganisms mentioned hereinbefore, such as S. aureus (e.g. Methicillinresistant S. aureus (MRSA))).

Particular bacterial conditions that may be treated by topicalpharmaceutical compositions and combination products according to thepresent invention also include the skin- and membrane-related conditionsdisclosed hereinbefore, as well as: acne vulgaris; rosacea (includingerythematotelangiectatic rosacea, papulopustular rosacea, phymatousrosacea and ocular rosacea); erysipelas; erythrasma; eethyma; eethymagangrenosum; impetigo; paronychia; cellulitis; folliculitis (includinghot tub folliculitis); furunculosis; carbunculosis; staphylococcalscalded skin syndrome; surgical scarlet fever; streptococcal peri-analdisease; streptococcal toxic shock syndrome; pitted keratolysis;trichomycosis axillaris; pyoderma; external canal ear infections; greennail syndrome; spirochetes; necrotizing fasciitis; Mycobacterial skininfections (such as lupus vulgaris, scrofuloderma, warty tuberculosis,tuberculides, erythema nodosum, erythema induratum, cutaneousmanifestations of tuberculoid leprosy or lepromatous leprosy, erythemanodosum leprosum, cutaneous M. kansasii, M. malmoense, M. szulgai, M.simiae, M. gordonae, M. haemophilum, M. avium, M. intracellulare, M.chelonae (including M. abscessus) or M. fortuitum infections, swimmingpool (or fish tank) granuloma, lymphadenitis and Buruli ulcer(Bairnsdale ulcer, Searles' ulcer, Kakerifu ulcer or Toro ulcer)); aswell as infected eczma, burns, abrasions and skin wounds.

Particular fungal conditions that may be treated by topicalpharmaceutical compositions and combination products according to thepresent invention also include the skin- and membrane-related conditionsdisclosed hereinbefore, as well as: candidiasis; sporotrichosis;ringworm (e.g. tinea pedis, tinea cruris, tinea capitis, tinea unguiumor tinea corporis); tinea versicolor; and infections with Trichophyton,Microsporum, Epidermophyton or Pityrosporum ovale fungi.

When employed to treat a microbial infection, the compounds of formulaeI, Ia, Ib or Ic, whether administered on their own or in combinationwith a conventional antimicrobial agent, are preferably administered ina smaller number of doses than is necessary for the treatment of thesame microbial infection utilising conventional antimicrobial agentsonly (e.g. in less than 7, 6, 5, 4, or 3 doses, such as in 2 doses or,particularly, 1 dose).

In this respect, a still further aspect of the invention provides amethod of reducing the dose of conventional antimicrobial agent requiredto treat a microbial infection, the method comprising co-administering acompound of formula I, Ia, Ib or Ic.

Compounds of formulae I, Ia, Ib and Ic have the advantage that they maybe used to kill clinically latent microorganisms. Further, in treatingmicrobial infections, compounds of formulae I, Ia, Ib and Ic may possessthe further advantage that they allow for a shorter period of therapy(either alone or in combination with a conventional antimicrobialagent), thus increasing patient compliance (through, for example, theneed to take fewer or smaller doses of antimicrobial agents) and/orminimising the risk of generating sub-populations of microorganisms thatare (genetically) resistant to conventional antimicrobial agents.

Additionally, compounds according to the invention may have theadvantage that they may be more efficacious than, be less toxic than,have a broader range of activity than, be more potent than, producefewer side effects than, or have other useful pharmacological propertiesover compounds known in the prior art.

Biological Tests

Test procedures that may be employed to determine the biological (e.g.bactericidal or antibacterial) activity of the compounds of formulae I,Ia, Ib and Ic include those known to persons skilled in the art fordetermining:

-   (a) bactericidal activity against stationary-phase or “persister”    bacteria (i.e. “clinically latent” bacteria); and-   (b) antibacterial activity against log phase bacteria.

In relation to (b) above, methods for determining activity against logphase bacteria include a determination, under standard conditions (i.e.conditions known to those skilled in the art, such as those descried inWO 2005/014585, the disclosures of which document are herebyincorporated by reference), of Minimum Inhibitory Concentration (“MIC”)or Minimum Bactericidal Concentration (“MBC”) for a test compound.

In relation to (a) above, methods for determining activity againstclinically latent bacteria include a determination, under conditionsknown to those skilled in the art (such as those described in NatureReviews, Drug Discovery 1, 895-910 (2002), the disclosures of which arehereby incorporated by reference), of Minimum Stationary-cidalConcentration (“MSC”) or Minimum Dormicidal Concentration (“MDC”) for atest compound. Specific examples of such methods are described below.

Protocol for Pyogenic Bacteria

Bacterial Strains

The strains used for screening are shown in the following table.

Staphylococcus aureus (Oxford) Gram positive Reference strainEscherichia coli K12 Gram negative Reference strain Enterococcus Grampositive Clinical isolate Pseudomonas Gram negative Clinical isolateMethicillin resistant S. aureus Gram positive Clinical isolate (MRSA)Klebsiella aerogrenes Gram negative Clinical isolate E. coli Gramnegative Clinical isolate Streptococcus pneumoniae Gram positiveReference strain Streptococcus pyogenes Group A Gram positive Referencestrain Streptococci Group B streptococci (Streptococcus Gram positiveReference strain agalactiae) Streptococcus viridans Gram positiveReference strain Haemophilus influenzae Gram negative Reference strain

Growth of Bacteria

The bacteria (except for streptococci and H. influenzae) were grown in10 mL of nutrient broth (No. 2 (Oxoid)) overnight at 37° C., withcontinuous shaking at 120 rpm. Streptococci and H. influenzae were grownovernight in Todd-Hewitt broth (Sigma) without shaking The overnightcultures were diluted (1000×) in 100 mL of growth medium and thenincubated with or without shaking for 10 days. Viability of the bacteriawas estimated by colony forming unit (CFU) counts at 2 hours intervalsat the first 24 hours and at 12-24 hours afterwards. From serial 10-folddilutions of the experimental cultures, 100 μL samples were added totriplicate plates of nutrient agar plates (Oxoid) and blood agar plates(Oxoid). Colony forming units (CFU) were counted after incubation of theplates at 37° C. for 24 hours.

Log-Phase Cultures:

The above-described overnight cultures were diluted (1000×) withiso-sensitest broth. The cultures were then incubated at 37° C. withshaking for 1-2 hours to reach log CFU 6, which served as log-phasecultures.

Stationary Phase Cultures:

Cultures incubated for more than 24 hours are in stationary phase. Fordrug screening, 5-6 day old stationary phase cultures are used as shownin FIG. 1 (the periods between two arrows).

Measurements of Bactericidal Activity Against Log-Phase Cultures

Different concentrations of each test compound were incubated with thelog-phase cultures in 96 well plates for various periods of time (2, 4,6, 12, 24 hours).

Bactericidal activity was then examined by taking a spectrophotometerreading (using a plate reader) of the resulting cultures, as well as byCFU counts as described above.

Measurements of Bactericidal Activity Against Stationary-Phase Cultures

Different concentrations of each test compound were incubated withstationary phase cultures (5-6 day cultures) in 96 well plates for 24 or48 hours. Bactericidal activity was then determined by taking CFU countsof the resulting cultures, as described above.

Measurements of Bactericidal Activity Against Persistent Bacteria

An antibiotic (e.g. gentamicin) was added to 5-6 day stationary-phasecultures to the final concentration of 50 to 100 μg/mL for 24 hours.After 24 hours of antibiotic treatment, the cells are washed 3 timeswith phosphate buffered saline (PBS), and then resuspended in PBS. Thesurviving bacterial cells are used as persisters. Viability is estimatedby CFU counts. The persisters were then used in measurements ofbactericidal activity for test compounds.

Different concentrations of each test compound were incubated with the(persister) cell suspension in 96 well plates for various periods oftime (24 and 48 hours). Bactericidal activity was then determined bytaking CFU counts of the resulting cultures, as described above.

Protocol for M. tuberculosis

Growth of M. tuberculosis

M. tuberculosis H37Rv was grown in 10 mL of Middlebrook 7H9 brothcontaining 0.05% Tween 80 supplemented with 10% ADC without disturbingfor up to 100 days. In order to obtain evenly dispersed cultures priorto experimental treatment, clumps in the cultures were broken up byvortexing the cultures in the presence of 2 mm glass beads (PhilipHarris Scientific, Staffordshire, UK) for 2 minutes, followed bysonication in a water bath sonicator (Branson Ultrasonic B. V.) for 5minutes. The numbers of viable M. tuberculosis in the cultures weredetermined by colony forming unit (CFU) counts on Middlebrook 7H11 agar.Serials of 10-fold dilutions of the cultures are made in Middlebrook 7H9broth with 0.05% (v/v) Tween 80 but without ADC. Then, 100 μL of sampleswas added to one-third segments of the agar plates in duplicate. Theplates were incubated in polythene bags for 3 weeks at 37° C.

Measurements of Bactericidal Activity Against Log-Phase Cultures

Different concentrations of each test compound were incubated withlog-phase cultures (4 day cultures) for various time periods (4, 8, 16,24 days). Bactericidal activity was then determined by taking CFU countsof the resulting cultures, as described above.

Measurements of Bactericidal Activity Against Stationary-Phase Culturesand Persistent Bacteria

Model 1—Stationary-Phase Cultures.

Different concentrations of each test compound were incubated with thesonicated 100-day cultures, each concentration to a separate 10 mLculture. After incubation for 5 days, counts of viable CFU weredetermined by inoculating a pair of 7H11 plates with 100 μL it of10-fold serial dilutions of the resulting cultures.

Model 2—Persistent Bacteria Selected by Rifampicin.

Rifampicin (100 mg/L) was added to each of a set of sonicated 100-daycultures, which cultures were then incubated for 5 days. After the firstday of incubation, no colonies could be obtained on plates inoculatedfrom the culture. After washing twice with PBS by centrifugation, fresh(and rifampicin-free) 7H9 medium was added to make up the volume to 10mL and the test compound was added in the same concentrations as inmodel 1. After further incubation for 7 days, CFU counts were determinedby inoculating 1 mL from each container onto a 7H11 plate. These plateswere then incubated for 2 weeks and the very small colonies were countedand marked. After a further 2 weeks of incubation, any additionalunmarked colonies (i.e. those that grew slowly) were added to thecounts. Control studies have shown that plate counts begin to yieldcolonies on subculture after about 4 days of incubation of therifampicin-free cultures.

Model 3.

The procedure is similar to model 2, but only different concentrationsof the test compound was added to the 100-day culture at three daysafter the rifampicin treatment. At the end of the 7-day incubationperiod (4 days with candidate drugs plus rifampicin), all cultures werewashed, replacing with medium free of test compound, and then wereincubated for a further 7 days before CFU counts were determined.

Skin (Topical) Models

In addition to in vitro testing against stationary- and log-phasebacteria, compounds of formulae I, Ia, Ib and Ic may also be tested invarious in vivo models, including those known to those skilled in theart. For example, for determination of compound activity againstbacteria in or on the skin, protocols that may be followed include thosedescribed in Antimicrobial Agents and Chemotherapy 49(8), 3435-41(2005), as well as the following.

Mouse Superficial Skin Bacterial Model (Intact Skin)

ICR or BALB/c mice aged 6-8 weeks are obtained from Harlan UK. The miceare anesthetized by intraperitoneal injection of 200 μL, of Ketaminehydrochloride/Xylazine solution. Fur on the back of the mouse is removedusing an electrical clipper. A 2 cm² (2 cm×1 cm) area of skin is markedwith a marker pen. The marked skin area is swabbed using a disposableswab for 3 times in order to examine the bacterial numbers on the skin.The bacteria on the swab will spread on blood agar plates (Oxoid™).

Log-phase or stationary phase bacterial cultures will be used. Thecultures will be concentrated by centrifugation to obtain 10⁹ to 10¹⁰CFU/mL. The cell pellet will be resuspended with nutrient broth or PBSand glycerol (50%). 15-20 μL, of the cell suspension is added to theskin area (2 cm²) which gives 10⁶⁻⁷ CFU on the skin. The skin is allowedto dry for about 15 min. Solutions of test compound at differentconcentrations will be applied on the skin area for different periods oftime.

Bacterial numbers on the skin will be estimated as follows: After themouse has been euthanised, the skin at the marked area will be cut andadded into a 2 mL tube containing 1 mL water and glass beads (1 mm). Theskin will be homogenised using a reciprocal shaker (Hybaid Ltd, UK) for45 seconds (speed setting 6.5) or votexing for 1 min. Residual testcompound will be removed by washing 3 times with water or PBS (if thetest compound precipitates in the buffer system, water alone is used forwashing). CFU counts will be performed after a serial of 10 folddilution of the homogenates. 100 μL samples will be added to one thirdof blood agar plates (Oxoid™) in duplicate. Colony forming units (CFU)will then be counted using aCoLye (a colony counter) after incubation ofthe plates at 37° C. for 24 hours.

Mouse Superficial Skin Infection Model (Tape-Stripping Infection Model)

ICR or BALB/c mice aged 6-8 weeks are obtained from Harlan UK. The miceare anesthetized by intraperitoneal injection of 200 μL of Ketaminehydrochloride/Xylazine solution. The fur of the mice on the back will beremoved by electric clipper. An area of 2 cm² skin is tape-strippedusing autoclave tape. The skin will be striped 10 times in succession.After this procedure, the skin become visibly damaged and ischaracterized by reddening and glistening but no regular bleeding.Buprenorphine will be given during the anaesthetic period and every 12hours for up to 3 days to reduce prolonged pain. After stripping of theskin, a bacterial infection is initiated by placing a 10 μL of bacterialcell suspension containing 10⁷ cells from overnight or stationary phasecultures on the damaged skin area. At 0 and 4 hours after infection, 3mice will be killed to estimate the CFU counts on the skin. After 24hours, solutions of test compound at different concentrations will beapplied on the skin area for different periods of time. The experimentswill be terminated 18 h after the last topical treatment.

Bacterial numbers of the wounds will be estimated as follow: After themouse has been euthanised, the wounds, approximately 2 cm² will be cutand added to a 2 mL tube containing 1 mL water and glass beads (1 mm).The skin will be homogenised using a reciprocal shaker (Hybaid Ltd, UK)for 45 seconds (speed setting 6.5). Residual test compound will beremoved by washing 3 times with water. CFU counts will be performedafter a serial of 10 fold dilution of the homogenises. 100 μL samplesare added to one third of blood agar plates (Oxoid™) in duplicate.Colony forming units (CFU) are counted using aCoLye (a colony counter)after incubation of the plates at 37° C. for 24 hours.

The invention is illustrated, but in no way limited, by the followingexamples and by reference to the figures, which present data relating,inter alia, to the biological studies described above.

FIG. 1 illustrates typical growth curves for S. aureus and E. coli.

FIG. 2 illustrates a typical growth curve for M. tuberculosis H37R^(v).

FIG. 3 illustrates the effects of various known antibiotics (Augmentin™,levofloxacin, azithromycin and linezolid), and of certain compounds ofthe present invention, against stationary phase Staphylococcus aureus.The bacterium was grown in nutrient broth medium with shaking for 5days. The drugs were incubated with the bacterium for 24 hours. CFUcounts were then performed on the drug treated cells and the control(drug free) cells.

FIG. 4 illustrates the effects of vancomycin and certain compounds ofthe present invention against stationary phase stationary phaseMethicillin Resistant Staphylococcus aureus (MRSA). The bacterium wasgrown in nutrient broth medium with shaking for 5 days. The drugs wereincubated with the bacterium for 24 hours. CFU counts were performed onthe drug treated cells and the control (drug free) cells.

Key (FIGS. 3 and 4)

HT31:

-   1-(Indan-2-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline.

HT42:

-   4-Methyl-2-phenylethyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-d]quinoline.

EXAMPLES General Experimental Procedure

Analytical LC-MS data were obtained using either Method A or Method B asindicated.

Method A: A Hewlett Packard HP1100 LC system using a 30×4.6 mm 3 micronPhenomenex Luna C18 column eluting at 2 mL/min with a gradient (5-95%over 4 minutes) of MeCN/water (+0.1% formic acid). Detection by massspectrometry used a Micromass Platform LC quadrupole instrument in bothpositive and negative electrospray mode. Detection was also performedusing a Sedex 65 evaporative light scattering detector and an HP1100Diode array detector.

Method B: A Hewlett Packard 1050 LC system using a 100×3 mm 5 micronHiggins Clipeus C18 column eluting at 2 mL/min with a gradient (5 to 95%over 15 minutes) of MeCN/water (+0.1% formic acid). Detection by massspectrometry used a Finnigan TSQ700 triple quadrupole instrument inpositive electrospray mode. Detection was also performed by UVabsorption at 254 nm.

Starting Materials

The following, commercially available compounds may be employed in thesyntheses described below.

List 1 2,4-Dimethoxyaniline. 4-Chloroaniline. 4-Methoxyaniline.4-(Morpholin-4-yl)aniline. 4-Phenoxyaniline. Ethyl 4-aminophenylacetate.2-Phenoxyaniline. Methyl 4-aminobenzoate. 4-Ethoxyaniline.4-Cyanoaniline. 4-Trifluoromethoxyaniline. 4-Hydroxyaniline.4-(Piperidin-1-yl)aniline.

List 2 Cyclopropylamine. Aniline. 3-Phenoxyaniline. 4-Phenoxyaniline.4-(2-Dimethylaminoethoxy)aniline. 4-(Pyridin-3-yloxy)aniline.1-Benzyl-piperidin-4-ylamine. Indan-2-ylamine. Benzylamine.2-Phenylethylamine. 2-Phenoxyethylamine. 4-Hydroxyaniline.4-Methoxyaniline. 3-Hydroxyaniline. 3-Hydroxy-5-methylaniline.5-Amino-2-phenoxypyridine. Indan-1-ylamine. 3,4-Methylenedioxaniline.3-Methylbutylamine. 5-Amino-2-methoxypyridine. 4-iso-Propylaniline.Cyclopropylmethylamine. 4-Bromo-3-fluoroaniline.Benzodioxan-2-ylmethylamine. 1-Amino-1,2,3,4- Cyclohexylamine.tetrahydronaphthalene. 2-Methylbenzylamine. 1-Phenylethylamine.4-(4-Fluorophenoxy)aniline. 4-(Piperidin-1-yl)aniline.2-Pyridylmethylamine. 2-(3-Pyridyl)ethylamine.1-(3-Aminopropyl)pyrrolidin- (5-Methylpyrazin-2-yl)methylamine. 2-one.2-(2-Pyridyl)ethylamine. Ethyl 3-aminopropionate Ethyl 4-aminobutanoate.Methyl 3-aminopropionate. Methyl 4-aminobutanoate. Ethyl aminoacetate.4-Amino-1-methylpiperidine. 1-Benzyl-3-aminopyrrolidine.3-Methoxypropylamine. Tetrahydrofuran-2-ylmethylamine.2-(4-Chlorophenyl)ethylamine. 2-(4-Methoxyphenyl)ethylamine.2-Phenylpropylamine.

Preparations Preparation 1

The compounds listed below were prepared by the following generalmethod.

The relevant aniline (0.05 mol; see List 1) and 2-acetyl-5-butyrolactone(0.05 mol) were heated to 120° C. for one hour, and then heated to 160°C. for two hours. After cooling to room temperature, phosphoryl chloride(50 mL) was added and the mixture heated at reflux for one hour. Aftercooling to room temperature again, the mixture was poured onto crushedice (100 g) and neutralised with sodium carbonate (added as a solid).The resulting oily product was extracted into dichloromethane (50 mL)and the organic solution washed with water (25 mL), then brine (25 mL)and dried with anhydrous magnesium sulphate. Filtration and evaporationgave a brown solid, recrystallisation of which from ethanol gave thetarget substituted 4-chloro-3-(2-chloroethyl)-2-methylquinoline as acolourless or off-white solid.

(a) 4-Chloro-3-(2-chloroethyl)-6,8-dimethoxy-2-methylquinoline

LCMS (Method A): Rt=3.17 min, m/z=300.06 [M+H]⁺; C₁₄H₁₅Cl₂NO₂,Mono-isotopic mass=299.1.

(b) 4-Chloro-3-(2-chloroethyl)-6-methoxy-2-methylquinoline

LCMS (Method A): Rt=3.16 min, m/z=269.98 [M+H]⁺; C₁₃H₁₃Cl₂NO,Mono-isotopic mass=269.0.

(c) 4-Chloro-3-(2-chloroethyl)-2-methyl-6-phenoxyquinoline

LCMS (Method A): Rt=4.38 min, m/z=332.00 [M+H]⁺; C₁₈H₁₅Cl₂NO,Mono-isotopic mass=331.05.

(d) 4-Chloro-3-(2-chloroethyl)-2-methyl-8-phenoxyquinoline

LCMS (Method A): Rt=4.27 min, m/z=332.01 [M+H]⁺; C₁₈H₁₅Cl₂NO,Mono-isotopic mass=331.05.

(e) 4-Chloro-3-(2-chloroethyl)-6-ethoxy-2-methylquinoline

LCMS (Method A): Rt=3.54 min, m/z=284.16 [M+H]⁺; C₁₄H₁₅Cl₂NO,Mono-isotopic mass=283.05.

(f) 4-Chloro-3-(2-chloroethyl)-2-methyl-6-(morpholin-4-yl)quinoline

¹H NMR (400 Mz, D₆DMSO) δ 7.82 (d, J=9.3 Hz, 1H), 7.65 (dd, J=9.3, 2.7Hz 1H), 7.23 (d, J=2.7 Hz, 1H), 3.88 (t, J=6.7 Hz, 2H), 3.79 (m, 4H),3.41 (t, J=6.7 Hz, 2H), 3.28 (m, 4H), 2.70 (s, 3H).

(g) 4-Chloro-3-(2-chloroethyl)-2-methyl-6-trifluoromethoxyquinoline

LCMS (method A): Rt=4.39 min, m/z=323.89 [M+H]⁺; C₁₃H₁₀Cl₂F₃N0,Mono-isotopic mass=323.01.

(h) 4-Chloro-3-(2-chloroethyl)-2-methylquinoline

LCMS (method A): Rt=3.14 min, m/z=240.13 [M+H]⁺; C₁₂H₁₁Cl₂N,Mono-isotopic mass=239.03.

(i) 4-Chloro-3-(2-chloroethyl)-2,8-dimethylquinoline

LCMS (method A): Rt=4.53 min, m/z=253.98 [M+H]⁺; C₁₃H₁₃Cl₂N,Mono-isotopic mass=253.04.

(j) 4-Chloro-3-(2-chloroethyl)-2-methyl-6-(piperidin-1-yl)quinoline

Used directly without purification.

-   (k) 3-(2-Chloroethyl)-4,6-dichloro-2-methylquinoline

¹H NMR (400 Mz, D₆DMSO) δ 8.13 (d, J=2.2 Hz, 1H), 8.00 (d, J=9.0 Hz,1H), 7.82 (dd, J=9.0 Hz, 2.2 Hz, 1H), 3.92 (t, J=7.6 Hz, 2H), 3.45 (t,J=7.6 Hz, 2H), 2.78 (s, 3H).

(l) Methyl 4-chloro-3-(2-chloroethyl)-2-methylquinolin-6-carboxylate

LCMS (method A): Rt=3.80 min, m/z=298.05 [M+H]⁺; C₁₄H₁₃Cl₂NO₂,Mono-isotopic mass=297.03.

(m) Ethyl 4-chloro-3-(2-chloroethyl)-2-methylquinolin-6-ylacetate

LCMS (method A): Rt=3.47 min, m/z=326.13 [M+H]⁺; C₁₆H₁₇Cl₂NO₂,Mono-isotopic mass=325.06.

(n) 4-Chloro-3-(2-chloroethyl)-6-cyano-2-methylquinoline

LCMS (method A): Rt=3.69 min, m/z=264.95 [M+H]⁺; C₁₃H₁₀Cl₂N₂,Mono-isotopic mass=264.02.

(O) 4-Chloro-3-(2-chloroethyl)-6-hydroxy-2-methylquinoline

Used directly without purification.

(p) 6-Bromo-4-chloro-3-(2-chloroethyl)-2-methylquinoline

¹H NMR (400 Mz, CDCl₃) δ 8.98 (d, J=9.1 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H),8.07 (dd, J=9.1, 2.4 Hz, 1H), 3.92 (t, J=6.1 Hz, 2H), 3.59 (t, J=6.1 Hz,2H), 3.31 (s, 3H).

Preparation 2 4-Chloro-3-(2-chloroethyl)-6-phenoxyquinoline

(i) Sodium (2-oxodihydrofuran-3-ylidene)methoxide

A solution of ethyl formate (4.51 g) and γ-butyrolactone (5.0 g) indiethyl ether (50 mL) was added dropwise to a suspension of sodiumhydride (60% oil dispersion, 2.56 g) in diethyl ether (100 mL)containing methanol (0.2 mL) at such a rate as to maintain gentlereflux. The resultant mixture was then stirred at room temperature for48 hours. The mixture was evaporated to dryness and the residue wastriturated with cyclohexane and the solid was collected by filtration togive the sub-title compound (7.46 g) as a white powder.

¹H NMR (400 Mz, D₂O) δ 8.35 (m, 1H), 4.25 (m, 2H), 2.70 (m, 2H).

(ii) 3-[1-(4-Phenoxyphenylamino)methylidene]dihydrofuran-2-one

A mixture of sodium (2-oxodihydrofuran-3-ylidene)methoxide (1.0 g; seestep (i) above) and 4-phenoxyaniline hydrochloride (1.62 g) in methanol(20 mL) was stirred and heated at reflux for 30 minutes. The resultantcooled mixture was poured into water and the solid was collected byfiltration and washed with water and ethyl acetate. The resultant solidwas purified by chromatography on silica eluting with a mixture ofmethanol and dichloromethane (0:100 increasing to 1:20) to give thesub-title compound (0.69 g) as a white solid.

¹H NMR (400 Mz, D₆-DMSO) δ 9.06 (d, J=13.7 Hz, 1H), 7.62 (dt, J=13.4,2.1 Hz, 1H), 7.36 (m, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.09 (m, 1H), 6.96(m, 4H), 4.29 (t, J=7.6, 2H), 2.86 (td, J=7.6, 2.1 Hz, 2H).

(iii) 4-Chloro-3-(2-chloroethyl)-6-phenoxyquinoline

A mixture of 3-[1-(4-phenoxyphenylamino)methylidene]dihydrofuran-2-one(0.2 g; see step (ii) above) and phosphorus oxychloride was stirred andheated at reflux for 30 minutes. The resultant cooled mixture was addedcarefully to water with ice cooling as required and extracted withdiethyl ether. The organic phase was washed with aqueous brine solution,dried (MgSO₄) and filtered. The filtrate was evaporated to dryness andthe residue was purified by chromatography eluting with a mixture ofethyl acetate and cyclohexane (1:3) to give the title compound (0.116 g)as a pale yellow oil.

¹H NMR (400 Mz, CDCl₃) δ 8.69 (s, 1H), 8.09 (d, J=9.2 Hz, 1H), 7.67 (d,J=2.6 Hz, 1H), 7.49 (dd, J=9.2, 2.6 Hz, 1H), 7.41 (m, 2H), 7.21 (m, 1H),7.11 (m, 2H), 3.83 (t, J=7.1, 2H), 3.40 (t, J=7.1 Hz, 2H).

Preparation 3 3-[1-(4-Phenoxyphenylamino)ethylidene]dihydrofuran-2-one

Large Scale Process Outline.

Step No. Operation Charges 1 Set-up 10 L flange flask equipped withDean-Stark separator (250 mL volume). 2 Charge to flask 4-phenoxyaniline(1 eq). 1100 g 3 Charge to flask 2-acetylbutyrolactone (1.1 eq). 703 mL4 Charge to flask Amberlyst 15 ion exchange resin. 110 g 5 Charge toflask toluene (3 volumes) and agitate. 3300 mL 6 Heat reaction vessel toreflux. (Reflux temperature initially ~100° C. and as water is removedreflux temperature will increase to ~118° C.) 7 The reaction was stirredat reflux overnight. (When ~200 mL of water has collected in Dean-Starktrap remove sample concentrate in vacuo and analyse using ¹H NMR) 8Reaction allowed to cool to 50° C. 9 The reaction mixture was filteredto remove the resin. Some precipitation of the product will occur in theBüchner flask. Addition of DCM will dissolve the material. Combine DCMmixture with toluene filtrate for concentration. 10 Concentrate thereaction mixture in vacuo. Divide the reaction mixture between severalRB flasks. 11 Dry the crude solid in a vacuum oven overnight at 50° C.12 The crude solid was recrystallised from absolute EtOH 8800 mL (8volumes). (Dissolved at 65-70° C. and on cooling precipitated at ~50°C.)

Preparation 4 4-Chloro-3-(2-chloroethyl)-2-methyl-6-phenoxyquinoline

Large Scale Process Outline

Step No. Operation Charges 1 Set-up 10 L flange flask equipped with HClscrubber. 2 Charge to flask 3-[1-(4-phenoxyphenylamino)- 709 gethylidene]dihydrofuran-2-one (1 eq.; see Preparation 3 above). 3 Chargeto flask toluene (5 volumes). 3550 mL 4 Charge to flask phosphorusoxychloride (2 eq). 448 mL 5 The reaction flask was heated to 70° C. andthen gradually to 90° C. at which point a slow exotherm increased thereaction temperature to reflux. 6 The reaction temperature wasmaintained at 100° C. for 2 h, monitored for completion using LCanalysis. Reaction deemed complete when <1% of 3-[1-(4-phenoxy-phenylamino)ethylidene]dihydrofuran- 2-one present. Longerstir out if >1%. NB Gas evolution observed at this stage. 7 The reactionwas allowed to cool to 50° C. and 3550 mL added water dropwise initially(5 volumes). Reaction will exotherm and can be controlled by addition ofwater. NB Gas evolution observed at this stage. 8 The reaction mixturewas neutralised by addition of ~1150 g potassium carbonate. 9 Thereaction mixture was filtered to remove inorganic solids. 10 The toluenelayer was separated, dried over MgSO₄ and concentrated in vacuo to yieldthe crude product. NB Concentrate in batches of 1 L and remove solidfrom the flask before concentrating any further toluene. 11 Dry thecrude solid in a vacuum oven overnight at 50° C. 12 Grind the crudesolid into a powder using a pestle and mortar. 13 The crude solid wasslurried in MeOH (5 volumes) 3550 mL for 2 h at reflux, allowed to coolto room temperature and filtered to give the title compound, which wasdried in a vacuum oven at 50° C. to constant weight.

Synthesis of Compounds of Formula I Example 1

The compounds listed below were prepared by any one of the followingthree general methods. The crude compounds were then purified by any oneof the purification methods described below.

General Method 1

The relevant substituted 4-chloro-3-(2-chloroethyl)-2-methylquinoline(0.5 mmol; see Preparation 1 above) and the desired primary amine oraniline (1.0 mmol; see List 2 above) were heated at reflux in butanolfor 48 hours. The solvent was then evaporated prior to purification ofthe residue.

General Method 2

The relevant substituted 4-chloro-3-(2-chloroethyl)-2-methylquinoline(0.2 mmol; see Preparation 1 above) and the desired primary amine oraniline (0.4 mmol; see List 2 above) were dissolved in ethanol orn-butanol and heated to 170° C. in a sealed tube for up to 48 hours. Thesolvent was then evaporated prior to purification of the residue.

General Method 3

The relevant substituted 4-chloro-3-(2-chloroethyl)-2-methylquinoline(0.55 mmol; see Preparation 1 above), and the desired primary amine oraniline (0.55 mmol; see List 2 above) were dissolved in n-butanol orethoxyethanol and heated to 220° C., using microwave irradiation, for 20min. The solvent was then evaporated prior to purification of theresidue.

Purification Method 1

The crude substituted 4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(obtained by any one of the three general methods described above) waspurified by preparative HPLC using a 150×20.6 mm 7 micron Genesis C18column eluting at 10 mL/min with a gradient of water/MeCN (+0.1%trifluoroacetic acid or 0.1% formic acid). The fractions containing thedesired product were concentrated in vacuo to give the desired productas a trifluoroacetate or formate salt.

Purification Method 2

The crude substituted 4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(obtained by any one of the three general methods described above) waspurified by automated preparative HPLC using a 250×10 mm 10 micron LunaC18 column eluting at 8 mL/min with a gradient of MeCN/water (+0.1%formic acid). The fractions containing the desired product wereconcentrated in vacuo to give the desired product as a formic acid salt.

Purification Method 3

The crude substituted 4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(obtained by any one of the three general methods described above) waspurified by flash chromatography eluting withdichloromethane/methanol/acetic acid/water (240:70:3:2). The fractionscontaining the desired product were concentrated in vacuo to give thedesired product as the free base.

Purification Method 4

The crude substituted 4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(obtained by any one of the three general methods described above) waspurified by flash chromatography eluting with a mixture of methanol anddichloromethane (from 1:99 up to 1:4). The fractions containing thedesired product were concentrated in vacuo to give the desired productas the free base.

(a)6,8-Dimethoxy-4-methyl-1-(3-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate

Prepared using General Method 1 and Purification Method 1.

LCMS (Method B): Rt=8.62 min, m/z=413.12 [M+H]⁺; C₂₆H₂₄N₂O₃,Mono-isotopic mass=412.18.

¹H-NMR (400 MHz, D₆-DMSO): δ 12.95 (s, 1H), 7.60 (t, J=8.1 Hz, 1H), 7.41(m, 2H), 7.31 (ddd, J=8.1, 2.2, 0.9 Hz, 1H), 7.24 (t, J=2.2 Hz, 1H),7.18 (m, 1H), 7.13 (ddd, J=8.1, 2.2, 0.9 Hz, 1H), 7.09 (d, J=2.4 Hz,1H), 7.06 (m, 2H), 5.97 (d, J=2.4 Hz, 1H), 4.39 (t, J=9.4 Hz, 2H), 4.06(s, 3H), 3.46 (s, 3H), 3.31 (t, J=9.4 Hz, 2H), 2.61 (s, 3H).

(b)6,8-Dimethoxy-4-methyl-1-(2-phenoxyethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=7.77 min, m/z=365.12 [M+H]⁺; C₂₂H₂₄N₂O₃,Mono-isotopic mass=364.18.

¹H-NMR (400 MHz, D₆-DMSO): δ 12.5 (s, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.27(m, 2H), 7.15 (d, J=2.3 Hz, 1H), 6.94 (m, 1H), 6.90 (m, 2H), 4.42 (t,J=5.5 Hz, 2H), 4.35 (t, J=5.5 Hz, 2H), 4.19 (t, J=9.7 Hz, 2H), 4.07 (s,3H), 3.87 (s, 3H), 3.15 (t, J=9.7 Hz, 2H), 2.51 (s, 3H).

(c)1-Cyclopropyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=6.42 min, m/z=285.12 [M+H]⁺; C₁₇H₂₀N₂O₂,Mono-isotopic mass=284.15.

¹H-NMR (400 MHz, D₆-DMSO): δ 12.54 (s, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.15(d, J=2.4 Hz, 1H), 4.06 (s, 3H), 4.03 (t, J=9.4 Hz, 2H), 3.91 (s, 3H),3.43 (m, 1H), 3.06 (t, J=9.4 Hz, 2H), 2.50 (s, 3H), 1.12 (m, 2H), 1.06(m, 2H).

(d)8-Methoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate

Prepared using General Method 3 and Purification Method 1.

LCMS (Method B): Rt=8.48 min, m/z=383.11 [M+H]⁺; C₂₅H₂₂N₂O₂,Mono-isotopic mass=382.17.

¹H-NMR (400 MHz, D₄-methanol): δ 7.70 (d, J=9.5 Hz, 1H), 7.53 (m, 2H),7.43 (m, 3H), 7.21 (m, 1H), 7.2 (m, 2H), 7.07 (m, 2H), 6.50 (d, J=2.8Hz, 1H), 4.42 (t, J=9.5 Hz, 2H), 3.48 (s, 3H), 3.40 (t, J=9.5 Hz, 2H),2.60 (s, 3H).

(e){2-[4-(8-Methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-1-yl)phenyoxy]ethyl}dimethylaminehydrochloride

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid followed by evaporation.

LCMS (Method B): Rt=4.63 min, m/z=378.18 [M+H]⁺; C₂₃H₂₇N₃O₂,Mono-isotopic mass=377.21.

¹H-NMR (400 MHz, D₄-methanol): δ 7.72 (d, J=9.3 Hz, 1H), 7.55 (m, 2H),7.42 (dd, J=9.3, 2.7 Hz, 1H), 7.29 (m, 2H), 6.44 (d, J=2.7 Hz, 1H), 4.47(t, J=4.9 Hz, 2H), 4.40 (t, J=9.4 Hz, 2H), 3.67 (t, J=4.9 Hz, 2H), 3.41(s, 3H), 3.40 (t, J=9.4 Hz, 2H), 3.02 (s, 6H), 2.61 (s, 3H).

(f)8-Methoxy-4-methyl-1-[4-(pyridin-3-yloxy)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate

Prepared using General Method 3 and Purification Method 1.

LCMS (Method B): Rt=6.60 min, m/z=384.12 [M+H]⁺; C₂₄H₂₁N₃O₂,Mono-isotopic mass=383.16

¹H-NMR (400 MHz, D₄-methanol): δ 8.54 (d, J=2.9 Hz, 1H), 8.51 (dd, J=5,1.3 Hz, 1H), 7.86 (ddd, J=8.6, 2.9, 1.3 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H),7.75 (ddd, J=8.6, 5.0, 0.6 Hz, 1H), 7.65 (m, 2H), 7.45 (dd, J=9.4, 2.8Hz, 1H), 7.38 (m, 2H), 6.50 (d, J=2.8 Hz, 1H), 4.45 (t, J=9.5 Hz, 2H),3.50 (s, 3H), 3.43 (t, J=9.5 Hz, 2H), 2.63 (s, 3H).

(g) 4-Methyl-8-phenoxy-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=7.95 min, m/z=353.10 [M+H]⁺; C₂₄H₂₀N₂O,Mono-isotopic mass=352.16.

¹H-NMR (400 MHz, D₆-DMSO): δ 14.26 (s, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.60(dd, J=9.2, 2.6 Hz, 1H), 7.32 (m, 7H), 7.18 (m, 1H), 6.85 (m, 2H), 6.29(d, J=2.6 Hz, 1H), 4.28 (t, J=9.5 Hz, 2H), 3.30 (t, J=9.5 Hz, 2H), 2.60(s, 3H).

(h) 1-Benzyl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

Prepared using General Method 2 and Purification Method 3. LCMS (MethodB): Rt=8.17 min, m/z=367.13 [M+H]⁺; C₂₅H₂₂N₂O, Mono-isotopicmass=366.17.

¹H-NMR (400 MHz, D₆-DMSO): δ 7.97 (d, J=9.3 Hz, 1H), 7.58 (dd, J=9.3,2.4 Hz, 1H), 7.33 (m, 3H), 7.27 (m, 3H), 7.17 (m, 1H), 7.07 (m, 2H),6.90 (m, 2H), 4.97 (s, 2H), 4.12 (t, J=9.6 Hz, 2H), 3.23 (t, J=9.6 Hz,2H), 2.53 (s, 3H).

(i)1-(Indan-2-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=8.87 min, m/z=393.17 [M+H]⁺; C₂₇H₂₄N₂O,Mono-isotopic mass=392.19.

¹H-NMR (400 MHz, D₆-DMSO): δ 7.95 (d, J=9.3 Hz, 1H), 7.75 (d, J=2.5 Hz,1H), 7.56 (dd, J=9.3, 2.5 Hz, 1H), 7.39 (m, 2H), 7.24 (m, 2H), 7.19 (m,2H), 7.14 (m, 1H), 7.10 (m, 2H), 5.24 (m, 1H), 3.78 (t, J=9.5 Hz, 2H),3.18 (dd, J=16.2, 5.7 Hz, 2H), 3.11 (dd, J=16.2, 7.5 Hz, 2H), 3.02 (t,J=9.5 Hz, 2H), 2.45 (s, 3H).

(j) 4-Methyl-6-phenoxy-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=8.11 min, m/z=353.12 [M+H]⁺; C₂₄H₂₀N₂O,Mono-isotopic mass=352.16.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.15 (s, 1H), 7.60 (m, 5H), 7.51 (m, 2H),7.30 (m, 1H), 7.21 (m, 2H), 7.16 (dd, J=8.5, 7.9 Hz, 1H), 7.08 (dd,J=7.9, 1.3 Hz, 1H), 6.68 (dd, J=8.5, 1.3 Hz, 1H), 4.44 (t, J=9.5 2H),3.39 (t, J=9.5 2H), 2.68 (s, 3H).

(k) 1-Benzyl-4-methyl-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=8.28 min, m/z=367.16 [M+H]⁺; C₂₅H₂₂N₂O,Mono-isotopic mass=366.17

¹H-NMR (400 MHz, D₆-DMSO): δ 12.84 (s, 1H), 7.75 (dd, J=8.8, 0.9 Hz,1H), 7.49 (m, 2H), 7.39 (m, 4H), 7.30 (m, 3H), 7.19 (m, 2H), 7.10 (dd,J=7.9, 0.9 Hz, 1H), 5.24 (s, 2H), 4.18 (t, J=9.6 Hz, 2H), 3.27 (t, J=9.6Hz, 2H), 2.58 (s, 3H).

(1)1-(Indan-2-yl)-4-methyl-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=8.95 min, m/z=393.17 [M+H]⁺; C₂₇H₂₄N₂O,Mono-isotopic mass=392.19.

¹H-NMR (400 MHz, D₆-DMSO): δ 12.75 (s, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.49(m, 3H), 7.31 (m, 3H), 7.22 (m, 5H), 5.61 (m, 1H), 3.94 (t, J=9.4 Hz,2H), 3.42 (dd, J=16.3, 7.5 Hz, 2H), 3.32 (dd, J=16.3, 5.5 Hz, 2H), 3.10(t, J=9.4 Hz, 2H), 2.53 (s, 3H).

(m)4-Methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3. The productwas then converted to the hydrochloride salt by addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (Method B): Rt=8.58 min, m/z=381.11 [M+H]⁺; C₂₆H₂₄N₂O,Mono-isotopic mass=380.19.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.91 (s, 1H) 8.03 (d, J=9.3 Hz, 1H), 7.67(dd, J=9.3, 2.4 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.45 (m, 2H), 7.21 (m,4H), 7.14 (m, 2H), 7.02 (m, 2H), 3.96 (t, J=9.6 Hz, 2H), 3.89 (t, J=7.6Hz, 2H), 3.08 (t, J=9.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.49 (s, 3H)

(n)8-Methoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS Method B; Rt=8.48 min, M+=383.15 [M+H]+; C₂₅H₂₂N₂O₂, Mono-isotopicmass=382.17.

¹H-NMR (400 MHz, D₆-DMSO): δ 14.22 (s, 1H), 7.97 (d, J=9.3 Hz, 1H), 7.60(m, 2H), 7.51 (dd, J=9.3, 2.7 Hz, 1H), 7.46 (m, 2H), 7.22 (m, 3H), 7.07(m, 2H), 6.36 (d, J=2.7 Hz, 1H), 4.38 (t, J=9.5 Hz, 2H), 3.45 (s, 3H),3.34 (t, J=9.5 Hz, J=2H), 2.61 (s, 3H).

(O)8-Methoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-6-oltrifluoroacetate

Prepared using General Method 2 and Purification Method 1 (aside-product from the preparation of Example 3 (viii) below).

LCMS (Method B): Rt=7.42 min, m/z=335.12 [M+H]⁺; C₂₁H₂₂N₂O₂,Mono-isotopic mass=334.17.

¹H-NMR (400 MHz, D₆-DMSO): δ 12.45 (s, 1H), 11.79 (s, 1H), 7.32 (m, 4H),7.23 (m, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 4.14 (t,J=7.5 Hz, 2H), 4.00 (t, J=9.7 Hz, 2H), 3.81 (s, 3H), 3.11 (t, J=7.5 Hz,2H), 3.08 (t, J=9.7 Hz, 2H), 2.49 (s, 3H).

(p)1-(1-Benzyl-piperidin-4-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinebis-trifluoroacetate

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=5.90 min, m/z=450.22 [M+H]⁺; C₃₀H₃₁N₃O,Mono-isotopic mass=449.25

1H-NMR (400 MHz, D₆-DMSO, NaOD): δ 7.79 (d, J=9.2 Hz, 1H), 7.46 (m, 2H),7.35 (m, 3H), 7.27 (m, 5H), 7.14 (m, 2H), 3.71 (m, 1H), 3.64 (t, J=9.4Hz, 2H), 3.40 (s, 2H), 2.97 (t, J=9.4 Hz, 2H), 2.74 (d, br, J=10.6 Hz,2H), 2.36 (s, 3H), 1.63 (m, 6H).

(q)1-(Indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=9.05 min, m/z=393.09 [M+H]⁺; C₂₇H₂₄N₂₀,Mono-isotopic mass=392.19.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.92 (s, 1H), 8.04 (d, J=9.3 Hz, 1H), 7.77(s, 1H), 7.67 (dd, J=9.3, 1.8 Hz, 1H), 7.41 (m, 2H), 7.32 (m, 2H), 7.24(m, 2H), 7.18 (m, 1H), 7.11 (m, 2H), 6.00 (t, J=7.0 Hz, 1H), 3.72 (m,1H), 3.57 (m, 1H), 3.05 (m, 3H), 2.83 (m, 1H), 2.50 (s, 3H), 2.22 (m,2H)

(r)1-(Benzodioxan-2-ylmethyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=8.57 min, m/z=425.10[M+H]⁺; C₂₇H₂₄N₂O₃,Mono-isotopic mass=424.18.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.99 (s, 1H), 8.02 (d, J=9.3 Hz, 1H), 7.72(d, J=2.4 Hz, 1H), 7.67 (dd, J=9.3, 2.4 Hz, 1H), 7.27 (m, 2H), 7.11 (m,1H), 7.05 (m, 2H), 6.88 (dd, J=8.0, 1.7 Hz, 1H), 6.83 (ddd, J=8.0, 7.1,1.7 Hz, 1H), 6.77 (ddd, J=8.0, 7.1, 1.7 Hz, 1H), 6.57 (dd, J=8.0, 1.7Hz, 1H), 4.57 (m, 1H), 4.25 (dd, J=11.5, 2.3 Hz, 1H), 4.18 (m, 1H), 4.02(m, 2H), 3.92 (dd, J=15.8, 3.7 Hz, 1H), 3.72 (dd, J=11.5, 7.3 Hz, 1H),3.17 (m, 2H), 2.52 (s, 3H).

(s)4-Methyl-8-phenoxy-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=9.12 min, m/z=407.20 [M+H]⁺; C₂₈H₂₆N₂O,Mono-isotopic mass=406.20

¹H-NMR (400 MHz, D₆-DMSO): δ 13.90 (s, br, 1H), 8.02 (d, J=9.3 Hz, 1H),7.67 (d, br, J=9.3 Hz, 1H), 7.48 (s, br, 1H), 7.36 (m, 2H), 7.13 (m,7H), 5.53 (s, br, 1H), 3.90 (s, br, 1H), 3.56 (s, br, 1H), 3.10 (t,J=9.6 Hz, 2H), 2.73 (m, br, 2H), 2.52 (s, 3H), 1.99 (m, br, 2H), 1.90(m, 1H), 1.68 (m, 1H).

(t)1-Cyclohexyl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

Prepared using General Method 3 and Purification Method 4.

LCMS (Method B): Rt=8.83 min, m/z=359.17 [M+H]⁺; C₂₄H₂₆N₂O,Mono-isotopic mass=358.20.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.80 (s, 1H), 8.02 (d, J=9.4 Hz, 1H), 7.72(dd, J=9.4, 2.6 Hz, 1H), 7.50 (m, 2H), 7.39 (d, J=2.6 Hz, 1H), 7.27 (m,1H), 7.21 (m, 2H), 3.98 (t, J=9.6 Hz, 2H), 3.96 (m, 1H), 3.07 (t, J=9.6Hz, 2H), 2.47 (s, 3H), 1.75 (d, J=12.0 Hz, 2H), 1.57 (m, 5H), 1.07 (m,1H), 0.87 (m, 2H).

(u)8-Ethoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate

Prepared using General Method 2 and Purification Method 2,

LCMS (Method B): Rt=8.94 min, m/z=397.15 [M+H]⁺; C₂₆H₂₄N₂O₂,Mono-isotopic mass=396.18.

¹H-NMR (400 MHz, D₄-methanol): δ 8.50 (br s, 1H), 7.71 (d, J=9.3 Hz,1H), 7.57 (t, J=8.1 Hz, 1H), 7.42 (dd, J=9.3, 2.6 Hz, 1H), 7.37 (m, 2H),7.24 (ddd, J=8.1, 2.2, 0.9 Hz, 1H), 7.16 (m, 1H), 7.12 (ddd, J=8.1, 2.2,0.9 Hz, 1H), 7.09 (t, J=2.2 Hz, 1H), 7.04 (m, 2H), 6.50 (d, J=2.6 Hz,1H), 4.39 (t, J=9.5 Hz, 2H), 3.67 (q, J=7.0 Hz, 2H), 3.37 (t, J=9.5 Hz,2H), 2.59 (s, 3H), 1.28 (t J=7.0 Hz, 3H).

Example 2

The following compounds were prepared, from appropriate intermediates(such as those described hereinbefore), according to or by analogy withmethods described herein:

(i)1-(4-methoxyphenyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 3 and Purification Method 1.

LCMS (Method B): Rt=8.14 min, m/z=383.11 [M+H]⁺; C₂₅H₂₂N₂O₂,Mono-isotopic mass=382.17.

¹H-NMR (400 MHz, D₄-methanol): δ 7.77 (d, J=9.2 Hz, 1H), 7.59 (dd,J=9.2, 2.6 Hz, 1H), 7.30 (m, 2H), 7.18 (m, 3H), 6.82 (m, 4H), 6.41 (d,J=2.6 Hz, 1H), 4.27 (t, J=9.5 Hz, 2H), 3.84 (s, 3H), 3.33 (t, J=9.5 Hz,2H), 2.58 (s, 3H).

(ii) 4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (Method B): Rt=8.34 min, m/z=353.10 [M+H]⁺; C₂₄H₂₀N₂O,Mono-isotopic mass=352.16.

¹H-NMR (400 MHz, D₆-DMSO): δ 14.0 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.82(m, 1H), 7.58 (m, 2H), 7.47 (m, 2H), 7.34 (m, 1H), 7.23 (m, 1H), 7.20(m, 2H), 7.16 (m, 2H), 7.06 (dd, J=8.7, 1.2 Hz, 1H), 4.38 (t, J=9.4 Hz,2H), 3.34 (t, J=9.4 Hz, 2H), 2.62 (s, 3H).

(iii)4-methyl-1-(2-methylphenyl)methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The Productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (Method B): Rt=8.48 min, m/z=381.17 [M+H]⁺; C₂₆H₂₄N₂O,Mono-isotopic mass=380.19.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.94 (s, br, 1H), 8.01 (d, J=9.2 Hz, 1H),7.63 (dd, J=9.2, 2.4 Hz, 1H), 7.25 (m, 2H), 7.16 (m, 3H), 7.10 (m, 1H),7.00 (m, 2H), 6.80 (m, 2H), 4.88 (s, 2H), 4.11 (t, J=9.6 Hz, 2H), 3.26(t, J=9.6 Hz, 2H), 2.55 (s, 3H), 2.02 (s, 3H).

(iv)4-methyl-8-phenoxy-1-(4-iso-propylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 3. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (Method B): Rt=9.29 min, m/z=395.18 [M+H]⁺; C₂₇H₂₆N₂O,Mono-isotopic mass=394.20.

¹H-NMR (400 MHz, D₆-DMSO): δ 14.1 (s, br, 1H), 8.05 (d, J=9.2 Hz, 1H),7.64 (dd, J=9.2, 2.6 Hz, 1H), 7.32 (m, 2H), 7.30 (m, 2H), 7.23 (m, 2H),7.13 (m, 1H), 6.86 (m, 2H), 6.49 (d, J=2.6 Hz, 1H), 4.30 (t, J=9.5 Hz,2H), 3.31 (t, J=9.5 Hz, 2H), 2.88 (hept, J=7.0 Hz, 1H), 2.61 (s, 3H),1.16 (d, J=7.0 Hz, 6H).

(v)4-methyl-8-phenoxy-1-(1-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=8.60 min, m/z=381.17 [M+H]⁺; C₂₆H₂₄N₂O,Mono-isotopic mass=380.19.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.5 (s, br, 1H), 7.86 (d, J=9.2 Hz, 1H),7.61 (dd, J=9.2, 2.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 7.41 (m, 2H), 7.29(m, 3H), 7.23 (m, 1H), 7.16 (m, 2H), 6.97 (m, 2H), 5.69 (q, J=6.8 Hz,1H), 4.20 (m, 1H), 3.96 (m, 1H), 3.19 (t, J=9.6 Hz, 2H), 2.50 (s, 3H),1.64 (d, J=6.8 Hz, 3H).

(vi)8-methoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate

Prepared using General Method 1 and Purification Method 2.

LCMS (Method B): Rt=7.44 min, m/z=319.14 [M+H]⁺; C₂₁H₂₂N₂O,Mono-isotopic mass=318.17.

¹H-NMR (400 MHz, D₄-methanol): δ 8.45 (s, 1H), 7.69 (d, J=9.2 Hz, 1H),7.50 (dd, J=9.2, 2.6 Hz, 1H), 7.42 (d, J=2.6 Hz, 1H), 7.29 (m, 4H), 7.22(m, 1H), 4.22 (t, J=7.2 Hz, 2H), 4.00 (t, J=9.6 Hz, 2H), 3.87 (s, 3H),3.21 (t, J=7.2 Hz, 2H), 3.14 (t, J=9.6 Hz, 2H), 2.49 (s, 3H).

Example 3

The following compounds were prepared, from appropriate intermediates(such as those described hereinbefore), according to or by analogy withmethods described herein:

(i)6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

Prepared using General Method 2 and Purification Method 3.

LCMS (Method B): Rt=6.43 min, m/z=337.13 [M+H]⁺; C₂₀H₂₀N₂O₃,Mono-isotopic mass=336.15.

¹H-NMR (400 MHz, D₆-DMSO): δ 9.50 (s, br, 1H), 7.07 (m, 2H), 6.81 (m,2H), 6.53 (d, J=2.6 Hz, 1H), 5.90 (d, J=2.6 Hz, 1H), 3.95 (t, J=9.2 Hz,2H), 3.84 (s, 3H), 3.32 (s, 3H), 3.16 (t, J=9.2 Hz, 2H), 2.42 (s, 3H).

(ii)6,8-dimethoxy-1-(3-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (Method B): Rt=6.68 min, m/z=337.09 [M+H]⁺; C₂₀H₂₀N₂O₃,Mono-isotopic mass=336.15.

¹H-NMR (400 MHz, D₆-DMSO): δ 8.18 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 6.65(m, 3H), 6.58 (t, J=2.2 Hz, 1H), 6.04 (d, J=2.5 Hz, 1H), 4.13 (t, J=9.2Hz, 2H), 3.90 (s, 3H), 3.39 (s, 3H), 3.21 (t, J=9.2 Hz, 2H), 2.48 (s,3H).

(iii)6,8-dimethoxy-1-(3-hydroxy-5-methylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (Method B): Rt=7.14 min, m/z=351.12 [M+H]⁺; C₂₁H₂₂N₂O₃,Mono-isotopic mass=350.16.

¹H-NMR (400 MHz, D₆-DMSO): δ 8.18 (s, 1 h), 6.64 (d, J=2.5 Hz, 1H), 6.46(m, 2H), 6.36 (t, J=2.0 Hz, 1H), 6.08 (d, J=2.5 Hz, 1H), 4.11 (t, J=9.2Hz, 2H), 3.89 (s, 3H), 3.41 (s, 3H), 3.20 (t, J=9.2 Hz, 2H), 2.46 (s,3H), 2.21 (s, 3H).

(iv)8-methoxy-1-(4-methoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 3 and Purification Method 1.

LCMS (Method B): Rt=7.03 min, m/z=321.12 [M+H]⁺; C₂₀H₂₀N₂O₂,Mono-isotopic mass=320.15

¹H-NMR (400 MHz, D₆-DMSO): δ 13.55 (s, 1H), 7.79 (d, J=9.3 Hz, 1H), 7.52(m, 2H), 7.49 (dd, J=9.3, 2.8 Hz, 1H), 7.17 (m, 2H), 6.31 (d, J=2.8 Hz,1H), 4.35 (t, J=9.5 Hz, 2H), 3.83 (s, 3H), 3.36 (s, 3H), 3.33 (t, J=9.5Hz, 2H), 2.57 (s, 3H).

(v)8-trifluoromethoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (Method B): Rt=8.95 min, m/z=437.10 [M+H]⁺; C₂₅H₁₉F₃N₂O₂,Mono-isotopic mass=436.14.

¹H-NMR (400 MHz, D₆-DMSO): δ 14.4 (s, br, 1H), 8.17 (d, J=9.4 Hz, 1H),7.86 (dd, J=9.4, 2.6 Hz, 1H), 7.62 (m, 2H), 7.46 (m, 2H), 7.23 (m, 3H),7.09 (m, 2H), 6.80 (m, 1H), 4.41 (t, J=9.5 Hz, 2H), 3.36 (t, J=9.5 Hz,2H), 2.64 (s, 3H).

(vi)6,8-dimethoxy-4-methyl-1-[4-(pyridin-3-yloxy)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=6.82 min, m/z=414.12 [M+H]⁺; C₂₅H₂₃N₃O₃,Mono-isotopic mass=413.17

¹H-NMR (400 MHz, D₆-DMSO): δ 12.9 (s, 1H), 8.45 (m, 2H), 7.61 (m, 2H),7.52 (m, 2H), 7.30 (m, 2H), 7.07 (d, J=2.4 Hz, 1H), 5.94 (d, J=2.4 Hz,1H), 4.39 (t, J=9.5 Hz, 2H), 4.06 (s, 3H), 3.43 (s, 3H), 3.33 (t, J=9.5Hz, 2H), 2.62 (s, 3H).

(vii)1-benzyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (Method B): Rt=7.39 min, m/z=335.13 [M+H]⁺; C₂₁H₂₂N₂O₂,Mono-isotopic mass=334.17

¹H-NMR (400 MHz, D6-DMSO): δ 8.22 (s, 1H), 7.38 (m, 4H), 7.28 (m, 1H),6.66 (d, J=2.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 4.93 (s, 2H), 3.92 (t,J=9.5 Hz, 2H), 3.87 (s, 3H), 3.44 (s, 3H), 3.14 (t, J=9.5 Hz, 2H), 2.41(s, 3H).

(viii)6,8-dimethoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate

Prepared using General Method 2 and Purification Method 2.

LCMS (Method B): Rt=7.82 min, m/z=349.14 [M+H]⁺; C₂₂H₂₄N₂O₂,Mono-isotopic mass=348.18.

¹H-NMR (400 MHz, D₆-DMSO): δ 8.22 (s, 1H), 7.31 (m, 4H), 7.22 (m, 1H),6.74 (d, J=2.5 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 3.90 (s, 3H), 3.85 (t,J=7.6 Hz, 2H), 3.77 (s, 3H), 3.76 (t, J=9.5 Hz, 2H), 3.03 (t, J=9.5 Hz,2H), 2.97 (t, J=7.6 Hz, 2H), 2.38 (s, 3H).

(ix)4-methyl-1-(2-phenylethyl)-8-trifluoromethoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (Method B): Rt=8.09 min, m/z=373.08 [M+H]⁺; C₂₁H₁₉F₃N₂O,Mono-isotopic mass=372.14

¹H-NMR (400 MHz, D6-DMSO): 13.95 (s, br, 1H), 8.06 (d, J=9.5 Hz, 1H),7.99 (d, J=2.3 Hz, 1H), 7.91 (m, 1H), 7.29 (m, 4H), 7.20 (m, 1H), 4.16(t, J=7.4 Hz, 2H), 4.06 (t, J=9.5 Hz, 2H), 3.12 (t, J=9.5 Hz, 2H), 3.08(t, J=7.4 Hz, 2H), 2.50 (s, 3H).

(x)6,8-dimethoxy-1-(indan-1-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2,

LCMS (Method B): Rt=8.19 min, m/z=361.14 [M+H]⁺; C₂₃H₂₄N₂O₂,Mono-isotopic mass=360.18.

¹H-NMR (400 MHz, D₆-DMSO): δ 8.20 (s, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.26(td, J=7.4, 1.5 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H),6.99 (d, J=2.4 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.07 (t, J=7.4 Hz, 1H),3.92 (s, 3H), 3.80 (s, 3H), 3.50 (q, J=10.0 Hz, 1H), 3.36 (td, J=10.0,7.4 Hz, 1H), 2.97 (m, 4H), 2.45 (m, 1H), 2.40 (s, 3H), 2.13 (m, 1H).

(xi)6,8-dimethoxy-4-methyl-1-[(6-phenoxy)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=7.86 min, m/z=414.12 [M+H]⁺; C₂₅H₂₃N₃O₃,Mono-isotopic mass=413.17.

¹H-NMR (400 MHz, D₆-DMSO): δ 13.01 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.10(d, J=8.7, 2.8 Hz, 1H), 7.47 (m, 2H), 7.28 (d, J=8.7 Hz, 1H), 7.26 (m,1H), 7.15 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 5.89 (d, J=2.4 Hz, 1H), 4.38(t, J=9.5 Hz, 2H), 4.06 (s, 3H), 3.47 (s, 3H), 3.34 (t, 2H), 2.64 (s,3H).

(xii)6,8-dimethoxy-1-[(6-methoxy)pyridin-3-yl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 2 and Purification Method 1.

LCMS (Method B): Rt=6.57 min, m/z=352.13 [M+H]⁺; C₂₀H₂₁N₃O₃,Mono-isotopic mass=351.16.

¹H-NMR (400 MHz, D₆-DMSO): δ 12.96 (s, 1H), 8.43 (dd, J=2.8, 0.5 Hz,1H), 7.95 (dd, J=8.8, 2.8 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.07 (dd,J=8.8, 0.5 Hz, 1H), 5.88 (d, J=2.4 Hz, 1H), 4.36 (t, J=9.4 Hz, 2H), 4.06(s, 3H), 3.92 (s, 3H), 3.39 (s, 3H), 3.33 (t, J=9.4 Hz, 2H), 2.63 (s,3H).

(xiii)1-(benzodioxol-5-ylmethyl)-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (Method B): Rt=7.39 min, m/z=379.16 [M+H]⁺; C₂₂H₂₂N₂O₄,Mono-isotopic mass=378.16

¹H-NMR (400 MHz, D₆-DMSO): δ 8.21 (s, 1H), 6.94 (d, J=1.7 Hz, 1H), 6.89(d, J=7.9 Hz, 1H), 6.86 (dd, J=7.9, 1.7 Hz, 1H), 6.67 (m, 2H), 5.99 (s,2H), 4.81 (s, 2H), 3.88 (s, 3H), 3.87 (t, J=9.5 Hz, 2H), 3.55 (s, 3H),3.11 (t, J=9.5 Hz, 2H), 2.40 (s, 3H).

Example 4

The following compounds were prepared, from appropriate intermediates(such as those described hereinbefore), according to or by analogy withmethods described herein:

(a)6,8-dimethoxy-4-methyl-1-(3-methylbutyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (method B): Rt=7.90 min, m/z=315.14[M+H]⁺; C₁₉H₂₆N₂O₂,Mono-isotopic mass=314.20

¹H NMR (400 MHz, D₆-DMSO) δ 8.21 (s, 1H), 6.83 (d, J=2.5 Hz, 1H), 6.79(d, J=2.5 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.82 (t, J=9.4 Hz, 2H),3.66 (m, 2H), 3.04 (t, J=9.4 Hz, 2H), 2.39 (s, 3H), 1.69 (m, 1H), 1.59(m, 2H), 0.95, (d, J=6.5 Hz, 6H).

(b)1-cyclopropylmethyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinetrifluoroacetate;

Prepared using General Method 2 and Purification Method 1.

LCMS (method B): Rt=7.04 min, m/z=299.13[M+H]⁺; C₁₈H₂₂N₂O₂,Mono-isotopic mass=298.17

¹H NMR (400 MHz, D₆-DMSO) δ 12.40 (br s, 1H), 7.15 (d, J=2.3 Hz, 1H),7.13 (d, J=2.3 Hz, 1H), 4.15 (t, J=9.5 Hz, 2H), 4.07 (s, 3H), 3.92 (s,3H), 3.86 (d, J=6.6 Hz, 2H), 3.13 (t, J=9.5/hz, 2H), 2.50 (s, 3H), 1.24(m, 1H), 0.61 (m, 2H) 0.41 (m, 2H).

(c)4-methyl-8-(morpholin-4-yl)-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (method B): Rt=8.21 min, m/z=438.15[M+H]⁺; C₂₈H₂₇N₃O₂,Mono-isotopic mass=437.21

¹H NMR (400 MHz, D₄-methanol) δ 8.54 (s, 1H), 7.69 (d, J=9.5 Hz, 1H),7.58 (dd, J=9.5, 2.6 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.36 (m, 2H), 7.16(m, 2H), 7.03 (m, 4H), 6.43 (d, J=2.6 Hz, 1H), 4.34 (t, J=9.3 Hz, 2H),3.74 (m, 4H), 3.33 (t, J=9.3 Hz, 2H), 2.89 (m, 4H) 2.56 (s, 3H).

(d)8-methoxy-4-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate;

Prepared using General Method 2 and Purification Method 2.

LCMS (method B): Rt=8.00 min, m/z=345.18[M+H]⁺; C₂₃H₂₄N₂O, Mono-isotopicmass=344.19

¹H NMR (400 MHz, D₄-methanol) δ 8.54 (s, 1H), 7.74 (d, J=9.5 Hz, 1H),7.34 (d, J=7.0 Hz, 1H), 7.17 (m, 5H), 5.52 (br s, 1H), 3.67 (br m, 5H),3.05 (t, J=9.4 Hz, 2H), 2.88 (m, 2H), 2.45 (s, 3H), 2.11 (m, 3H), 1.88(m, 1H).

(e) 4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.25 min, m/z=289.17[M+H]⁺; C₂₀H₂₀N₂, Mono-isotopicmass=288.16

¹H NMR (400 MHz, D₆-DMSO) δ 13.59 (s, 1H), 8.2 (d, J=8.6 Hz, 1H), 7.92(dd, J=8.7, 1.4 Hz, 1H), 7.86 (m, 1H), 7.55 (m, 1H), 7.33 (m, 4H), 7.23(m, 1H), 4.17 (t, J=7.4 Hz, 2H), 3.99 (m, 2H), 3.09 (m, 4H), 2.49 (s,3H).

(f)4,6-dimethyl-1-(2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.25 min, m/z=289.15[M+H]⁺; C₂₀H₂₀N₂, Mono-isotopicmass=288.16

¹H NMR (400 MHz, D₆-DMSO) δ 12.06 (s, 1H), 7.66 (dt, j=7.0, 1.1 Hz, 1H),7.52 (m, 3H), 7.46 (m, 1H), 7.14 (dd, J=8.6, 7.0 Hz, 1H), 6.68 (d, J=8.6Hz, 1H), 4.33 (m, 2H), 3.40 (m, 2H), 2.71 (s, 3H), 2.67 (s, 3H), 2.18(s, 3H).

(g)4,6-dimethyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.60 min, m/z=303.19[M+H]⁺; C₂₁H₂₂N₂, Mono-isotopicmass=302.18

¹H NMR (400 MHz, D₆-DMSO) δ 11.73 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.74(dt, J=7.2, 1.0 Hz, 1H), 7.47 (dd, J=8.6, 7.2 Hz, 1H), 7.33 (m, 4H),7.24 (m, 1H), 4.16 (t, J=7.5 Hz, 2H), 4.00 (m, 2H), 3.09 (m, 4H), 2.67(s, 3H), 2.58 (s, 3H).

(h)4-methyl-8-(piperidin-1-yl)-1-[4-(piperidin-1-yl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=8.10 min, m/z=427.17[M+H]⁺; C₂₈H₃₄N₄, Mono-isotopicmass=426.28

¹H NMR (400 MHz, D₄-methanol) δ 7.92 (m, 4H), 7.73 (m, 2H), 7.15 (br s,1H), 4.48 (t, J=9.4 Hz, 2H), 3.75 (t, J=5.5 Hz, 4H), 3.44 (t, J=9.4 Hz,2H), 3.22 (br t, J=5.5 Hz, 4H), 2.66 (s, 3H), 2.12 (m, 4H), 1.83 (m,6H), 1.66 (m, 2H).

(i)4-methyl-8-(piperidin-1-yl)-1-(3-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=9.32 min, m/z=436.14[M+H]⁺; C₂₉H₂₉N₃O, Mono-isotopicmass=435.23

¹H NMR (400 MHz, D₄-methanol) δ 7.99 (dd, J=9.5, 2.3 Hz, 1H), 7.90 (d,J=9.5 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.41 (m, 2H), 7.27 (dd, J=7.9,1.5 Hz, 1H), 7.20 (m, 2H), 7.16 (m, 2H), 7.10 (m, 2H), 4.46 (t, J=9.4Hz, 2H), 3.41 (t, J=9.4 Hz, 2H), 3.287 (t, J=5.5 Hz, 4H), 2.63 (s, 3H),1.88 (m, 4H), 1.70 (m, 2H).

(j)1-{4-[2-(N,N-dimethylamino)ethoxy]phenyl}-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=5.43 min, m/z=440.11[M+H]⁺; C₂₈H₂₉N₃O₂,Mono-isotopic mass=439.23

¹H NMR (400 MHz, D₄-methanol) δ 7.81 (d, J=9.2 Hz, 1H), 9.57 (dd, J=9.2,2.6 Hz, 1H), 7.32 (m, 4H), 7.20 (m, 1H), 7.01 (m, 2H), 6.85 (m, 2H),6.49 (d, J=2.6 Hz, 1H), 4.39 (t, J=5.0 Hz, 2H), 4.30 (t, 9.4H, 2H), 3.70(t, J=5.0 Hz, 2H), 3.36 (t, J=9.4 Hz, 2H), 3.03 (s, 6H), 2.61 (s, 3H).

(k)1-[4-(4-fluorophenoxy)phenyl]-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=8.43 min, m/z=401.06[M+H]⁺; C₂₅H₂₁FN₂O₂,Mono-isotopic mass=400.16

¹H NMR (400 MHz, D₄-methanol) δ 7.70 (d, J=9.4 Hz, 1H), 7.53 (m, 2H),7.43 (dd, J=9.4, 2.7 Hz, 1H), 7.18 (m, 4H), 7.09 (m, 2H), 6.48 (d, J=2.7Hz, 1H), 4.41 (t, J=9.6 Hz, 2H), 3047 (s, 3H), 3.40 (t, J=9.6 Hz, 2H),2.61 (s, 3H).

(l)1-(benzodioxan-2-ylmethyl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.31 min, m/z=363.02[M+H]⁺; C₂₂H₂₂N₂O₃,Mono-isotopic mass=362.16

¹H NMR (400 MHz, D₄-methanol) δ 7.71 (d, J=9.3 Hz, 1H), 7.67 (d, J=2.6Hz, 1H), 7.50 (dd J=9.3, 2.6 Hz, 1H), 6.88 (dd, J=8.0, 1.6 Hz, 1H), 6.82(m, 1H), 6.76 (m, 1H), 6.63 (dd, J=8.0, 1.6 Hz, 1H), 4.81 (m, 1H), 4.46(m, 2H), 4.24 (m, 3H), 4.12 (dd, J=15.8, 4.0 Hz, 1H), 3.83 (s, 3H), 3.25(t, J=9.7 Hz, 2H), 2.53 (s, 3H).

(m)1-cyclohexyl-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.38 min, m/z=297.13[M+H]⁺; C₁₉H₂₄N₂O, Mono-isotopicmass=296.19

¹H NMR (400 MHz, D₄-methanol) δ 7.70 (m, 1H), 7.52 (m, 2H), 4.54 (m,1H), 4.14 (t, J=9.6 Hz, 2H), 3.96 (s, 3H), 3.16 (t, J=9.6 Hz, 2H), 2.48(s, 3H), 2.12 (d, J=12.3 Hz, 2H), 1.98 (m, 2H), 1.80 (m, 3H), 1.54 (m,2H), 1.32 (m, 1H).

(n) 8-methoxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.75 min, m/z=291.08[M+H]⁺; C₁₉H₁₈N₂O, Mono-isotopicmass=290.14

¹H NMR (400 MHz, D₄-methanol) δ 7.72 (d, J=9.4 Hz, 1H), 7.64 (m, 2H),7.56 (m, 3H), 7.40 (dd, J=9.4, 2.7 Hz, 1H), 6.38 (d, J=2.7 Hz, 1H), 4.45(t, J=9.5 Hz, 2H), 3.42 (t, J=9.5 Hz, 2H), 3.33 (s, 3H), 2.62 (s, 3H).

(o)4-methyl-8-phenoxy-1-[4-(3-pyridyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.48 min, m/z=446.05[M+H]⁺; C₂₉H₂₃N₃O₂,Mono-isotopic mass=445.18

¹H NMR (400 MHz, D₄-methanol) δ 8.80 (d, J=2.7 Hz, 1H), 8.67 (d, J=5.7Hz, 1H), 8.24 (ddd, J=8.8, 2.7, 1.1 Hz, 1H), 8.09 (dd, J=8.8, 5.7 Hz,1H), 7.86 (d, J=9.2 Hz, 1H), 7.64 (dd, J=9.2, 2.6 Hz, 1H), 7.48 (m, 2H),7.40 (m, 2H), 7.28 (m, 1H), 7.23 (m, 2H), 6.91 (m, 2H), 6.47 (d, J=2.6Hz, 1H), 4.38 (t, J=9.5 Hz, 2H), 3.41 (t, J=9.5 Hz, 2H), 2.64 (s, 3H).

(p)4-methyl-8-phenoxy-1-[2-(3-pyridyl)ethyl]-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=5.48 min, m/z=382.13[M+H]⁺; C₂₅H₂₃N₃O, Mono-isotopicmass=381.18

¹H NMR (400 MHz, D₄-methanol) δ 8.78 (d, J=5.9 Hz, 1H), 8.75 (d, J=1.5Hz, 1H), 8.32 (dt, J=8.1, 1.5 Hz, 1H), 8.02 (dd, J=8.1, 5.9 Hz, 1H),7.86 (d, J=9.2 Hz, 1H), 7.66 (dd, J=9.2, 2.4 Hz, 1H), 7.56 (d, J=2.4 Hz,1H), 7.41 (m, 2H), 7.15 (m, 3H), 4.12 (m, 4H), 3.25 (m, 4H), 2.55 (s,3H).

(q)4-methyl-8-phenoxy-1-(2-pyridylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.72 min, m/z=368.10[M+H]⁺; C₂₄H₂₁N₃O, Mono-isotopicmass=367.17

¹H NMR (400 MHz, D₄-methanol) δ 8.75 (dd, J=5.8, 1.2 Hz, 1H), 8.43 (m,1H), 7.94 (m, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.68(dd, J=9.2, 2.5 Hz., 1H), 7.30 (m, 2H), 7.18 (m, 1H), 6.90 (m, 2H), 6.88(d, J=2.5 Hz, 1H), 5.33 (s, 2H), 4.22 (t, J=9.5 Hz, 2H), 3.37 (t, J=9.5Hz, 2H), 2.64 (s, 3H).

(r)4-methyl-1-(5-methylpyrazin-2-ylmethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.51 min, m/z=383.10[M+H]⁺; C₂₄H₂₂N₄O, Mono-isotopicmass=382.18

¹H NMR (400 MHz, D₄-methanol) δ 8.50 (s, 1H), 8.43 (s, 1H), 7.83 (d,J=9.2 Hz, 1H), 7.62 (dd, J=9.2, 2.4 Hz, 1H), 7.30 (m, 3H), 7.15 (m, 1H),6.92 (m, 2H), 5.13 (s, 2H), 4.20 (t, J=9.5 Hz, 2H), 3.29 (t, J=9.5 Hz,2H), 2.62 (s, 3H), 2.57 (s, 3H).

(s)8-chloro-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.55 min, m/z=323.05[M+H]⁺; C₂₀H₁₉ClN₂,Mono-isotopic mass=322.12.

¹H NMR (400 MHz, D₆-DMSO) δ 14.02 (s, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.98(d, J=9.2 Hz, 1H), 7.88 (dd, J=9.2, 2.2 Hz, 1H), 7.31 (m, 4H), 7.20 (m,1H), 4.15 (t, J=7.3 Hz, 2H), 4.08 (t, J=9.6 Hz, 2H), 3.10 (m, 4H), 2.49(s, 3H).

(t) methyl4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylatehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.17 min, m/z=347.08[M+H]⁺; C₂₂H₂₂N₂O₂,Mono-isotopic mass=346.17

¹H NMR (400 MHz, D₆-DMSO) δ 14.09 (s, 1H), 8.78 (d, J=1.6 Hz, 1H), 8.29(dd, J=8.9, 1.6 Hz, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.45 (m, 2H), 7.36 (m,2H), 7.25 (m, 1H), 4.19 (t, J=9.5 Hz, 2H), 4.12 (t, J=8.0 Hz, 2H), 3.95(s, 3H), 3.16 (m, 4H), 2.52 (s, 3H).

(u)4-methyl-8-(morpholin-1-yl)-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.26 min, m/z=374.14[M+H]⁺; C₂₄H₂₇N₃O, Mono-isotopicmass=373.22

¹H NMR (400 MHz, D₆-DMSO) δ 13.66 (s, 1H), 7.85 (d, J=9.5 Hz, 1H), 7.73(dd, J=9.5, 2.4 Hz, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 7.19 (d, J=2.4 Hz,1H), 4.16 (t, J=7.5 Hz, 2H), 4.00 (t, J=9.7 Hz, 2H), 3.75 (m, 4H), 3.12(m, 8H), 2.47 (s, 3H).

(v) ethyl[4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-yl]acetatehydrochloride

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.57 min, m/z=375.08[M+H]⁺; C₂₄H₂₆N₂O₂,Mono-isotopic mass=374.20

¹H NMR (400 MHz, D₆-DMSO) δ 13.67 (s, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 7.76 (dd, J=8.8, 1.6 Hz, 1H), 7.34 (m, 2H), 7.29 (m,2H), 7.21 (m, 1H), 4.16 (t, J=7.5 Hz, 2H), 4.11 (t, J=7.1 Hz, 2H), 4.03(t, J=9.5 Hz, 2H), 3.89 (s, 2H), 3.09 (m, 4H), 2.48 (s, 3H), 1.19 (t,J=7.1 Hz, 3H).

(w)1-[3-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-1-yl)propyl]-pyrrolidin-2-onehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.58 min, m/z=402.11[M+H]⁺; C₂₅H₂₇N₃O₂,Mono-isotopic mass=401.21

¹H NMR (400 MHz, D₄-methanol) δ 7.80 (d, J=9.3 Hz, 1H), 7.61 (dd, J=9.3,2.5 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.47 (m, 2H), 7.25 (m, 1H), 7.14(m, 2H), 4.14 (t, J=9.6 Hz, 2H), 3.72 (t, J=7.8 Hz, 2H), 3.42 (t, J=7.1Hz, 2H), 3.21 (m, 4H), 2.51 (s, 3H), 2.35 (t, J=8.1 Hz, 2H), 2.03 (m,2H), 1.90 (m, 2H).

(x)4-methyl-8-phenoxy-1-[2-(2-pyridyl)ethyl]-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.28 min, m/z=382.10[M+H]⁺; C₂₅H₂₃N₃O, Mono-isotopicmass=381.18

¹H NMR (400 MHz, D₄-methanol) δ 8.78 (dd, J=5.9, 1.3 Hz, 1H), 8.54 (td,J=8.0, 1.3 Hz, 1H), 7.99 (m, 1H), 7.86 (d, J=9.4 Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.65 (dd, J=9.4, 2.5 Hz, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.41 (m,2H), 7.16 (m, 3H), 4.26 (t, J=7.3 Hz, 2H), 4.07 (t, J=9.6 Hz, 2H), 3.48(t, J=7.3 Hz, 2H), 3.23 (t, J=9.6 Hz, 2H), 2.56 (s, 3H).

(y) ethyl3-(8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)propionatehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.21 min, m/z=315.07[M+H]⁺; C₁₈H₂₂N₂O₃,Mono-isotopic mass=314.16

¹H NMR (400 MHz, D₆-DMSO) δ 13.77 (s, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.57(dd, J=9.3, 2.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 4.19 (t, J=7.3 Hz, 2H),4.09 (m, 4H), 3.91 (s, 3H), 3.12 (t, J=9.6 Hz, 2H), 2.91 (t, J=7.3 Hz,2H), 2.48 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).

(z) ethyl4-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)butanoatehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.67 min, m/z=391.07[M+H]⁺; C₂₄H₂₆N₂O₃,Mono-isotopic mass=390.19

¹H NMR (400 MHz, CD₃CN) δ 14.80 (s, 1H), 8.37 (d, J=9.3 Hz, 1H), 7.54(dd, J=9.3, 2.5 Hz, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.43 (m, 2H), 7.22 (m,1H), 7.12 (m, 2H), 4.06 (q, J=7.1 Hz, 2H), 4.02 (t, J=9.6 Hz, 2H), 3.60(m, 2H), 3.09 (t, J=9.6 Hz, 2H), 2.55 (s, 3H), 2.14 (t, J=7.3 Hz, 2H),1.85 (m, 2H), 1.19 (t, J=7.1 Hz, 3H).

(aa) methyl4-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)butanoatehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.26 min, m/z=377.08[M+H]⁺; C₂₃H₂₄N₂O₃,Mono-isotopic mass=376.18

¹H NMR (400 MHz, D₄-methanol) δ 7.81 (d, J=9.3 Hz, 1H), 7.65 (dd, J=9.3,2.5 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 7.14(m, 2H), 4.12 (t, J=9.6 Hz, 2H), 3.67 (m, 2H), 3.65 (s, 3H), 3.19 (t,J=9.6 Hz, 2H), 2.50 (s, 3H), 2.18 (t, J=7.2 Hz, 2H), 1.90 (m, 2H).

(ab) ethyl(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)acetatehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.21 min, m/z=362.99[M+H]⁺; C₂₂H₂₂N₂O₃,Mono-isotopic mass=362.16

¹H NMR (400 MHz, CD₃CN) δ 14.92 (s, 1H), 8.40 (d, J=9.3 Hz, 1H), 7.54(dd, J=9.3, 2.5 Hz, 1H), 7.43 (m, 2H), 7.29 (d, J=2.5 Hz, 1H), 7.22 (m,1H), 7.06 (m, 2H), 4.46 (s, 2H), 4.04 (m, 4H), 3.15 (t, J=9.6 Hz, 2H),2.60 (s, 3H), 1.13 (t, J=7.0 Hz, 3H).

(ac)4-methyl-1-(1-methylpiperidin-4-yl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinedihydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=4.68 min, m/z=374.14[M+H]⁺; C₂₄H₂₇N₃O, Mono-isotopicmass=373.22

¹H NMR (400 MHz, D₆-DMSO) δ 14.04 (s, 1H), 11.05 (s, 1H), 8.06 (d, J=9.2Hz, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 7.26 (m, 1H), 7.15 (m, 2H), 4.63(m, 1H), 4.01 (t, J=9.6 Hz, 2H), 3.43 (d, J=12.0 Hz, 2H), 3.14 (t, J=9.6Hz, 2H), 2.85 (m, 2H), 2.69 (s, 3H), 2.52 (s, 3H), 2.31 (m, 2H), 2.00(d, J=13.0 Hz, 2H).

(ad)1-(1-benzylpyrrolidin-3-yl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=4.54 min, m/z=374.16[M+H]⁺; C₂₄H₂₇N₃O, Mono-isotopicmass=373.22

¹H NMR (400 MHz, D₆-DMSO+TFA-D) δ 7.90 (br d, J=9.0 Hz, 1H), 7.70-7.58(m, 3H), 7.56-7.40 (m, 4H), 5.80-5.55 (m, 1H), 4.50 (2br s, 2H), 4.16(m, 2H), 3.98 (2br s, 3H), 3.73 (m, 1H), 3.61 (m, 2H), 3.43 (m, 1H),3.17 (m, 2H), 2.51 (s, 3H), 2.48 (m, 2H).

(ae) methyl3-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)propionatehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.05 min, m/z=363.07[M+H]⁺; C₂₂H₂₂N₂O₃,Mono-isotopic mass=362.16

¹H NMR (400 MHz, D₄-methanol) δ 7.83 (d, J=9.3 Hz, 1H), 7.65 (dd, J=9.3,2.5 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.45 (m, 2H), 7.24 (m, 1H), 7.14(m, 2H), 4.13 (t, J=9.6 Hz, 2H), 3.97 (t, J=7.1 Hz, 2H), 3.65 (s, 3H),3.18 (t, J=9.6 Hz, 2H), 2.66 (t, J=7.1 Hz, 2H), 2.52 (s, 3H).

(af)1-((S)-indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

Prepared using General Method 2 and Purification Method 3. The productwas isolated as the acetate salt and then converted to the free base bypartitioning between aqueous sodium carbonate and dichloromethanefollowed by evaporation of the organic phase.

LCMS (method B): Rt=8.81 min, m/z=393.06[M+H]⁺; C₂₇H₂₄N₂O, Mono-isotopicmass=392.19

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=9.2 Hz, 1H), 7.64 (d, J=2.6 Hz,1H), 7.31 (m, 3H), 7.24 (m, 2H), 7.16 (m, 2H), 7.08 (m, 1H), 7.02 (m,2H), 5.88 (t, J=7.6 Hz, 1H), 3.46 (m, 2H), 3.00 (m, 3H), 2.85 (m, 1H),2.52 (s, 3H), 2.32 (m, 1H), 2.11 (m, 1H).

(ag)1-((R)-indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;

Prepared using General Method 2 and Purification Method 3. The productwas isolated as the acetate salt and then converted to the free base bypartitioning between aqueous sodium carbonate and dichloromethanefollowed by evaporation of the organic phase.

LCMS (method B): Rt=8.68 min, m/z=393.11[M+H]⁺; C₂₇H₂₄N₂O, Mono-isotopicmass=392.19

¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=9.2 Hz, 1H), 7.64 (d, J=2.6 Hz,1H), 7.31 (m, 3H), 7.24 (m, 2H), 7.16 (m, 2H), 7.08 (m, 1H), 7.02 (m,2H), 5.87 (t, J=7.6 Hz, 1H), 3.45 (m, 2H), 2.99 (m, 3H), 2.84 (m, 1H),2.52 (s, 3H), 2.32 (m, 1H), 2.11 (m, 1H).

(ah)1-(3-methoxypropyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.31 min, m/z=349.13[M+H]⁺; C₂₂H₂₄N₂O₂,Mono-isotopic mass=348.18

¹H NMR (400 MHz, D₆-DMSO) δ 13.76 (s, 1H), 8.00 (m, 1H), 7.68 (m, 2H),7.46 (m, 2H), 7.23 (m, 1H), 7.12 (m, 2H), 4.06 (t, J=9.6 Hz, 2H), 3.73(t, J=7.5 Hz, 2H), 3.22 (t, J=5.8 Hz, 2H), 3.14 (s, 3H), 3.13 (t, J=9.6Hz, 2H), 2.49 (s, 3H), 1.82 (m, 2H).

(ai)4-methyl-8-phenoxy-1-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=7.35 min, m/z=361.12[M+H]⁺; C₂₃H₂₄N₂O₂,Mono-isotopic mass=360.16

¹H NMR (400 MHz, D₆-DMSO) δ 13.83 (s, 1H), 8.01 (d, J=9.2 Hz, 1H), 7.71(dd, J=9.2, 2.5 Hz, 1H), 7.68 (d, J=2.5 Hz, 1H), 7.48 (m, 2H), 7.25 (m,1H), 7.16 (m, 2H), 4.15 (td, J=11.3, 7.9 Hz, 1H), 4.03 (m, 2H), 3.73 (d,J=6.0 Hz, 2H), 3.52 (t, J=6.7 Hz, 2H), 3.13 (m, 2H), 2.50 (s, 3H), 1.74(m, 3H), 1.27 (m, 1H).

(aj)1-[2-(4-chlorophenyl)ethyl]-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=8.91 min, m/z=415.08[M+H]⁺; C₂₆H₂₃ClN₂O,Mono-isotopic mass=414.15.

¹H NMR (400 MHz, D₆-DMSO) δ 13.82 (2s, 1H), 8.01 (m, 1H), 7.68 (dd,J=9.2, 2.5 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.45 (m, 2H), 7.26 (m, 2H),7.21 (m, 1H), 7.14 (m, 2H), 7.06 (m, 2H), 3.98 (t, J=9.6 Hz, 2H), 3.92(t, J=7.5 Hz, 2H), 3.10 (t, J=9.6 Hz, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.50(s, 3H).

(ak)1-[2-(4-methoxyphenyl)ethyl]-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=8.44 min, m/z=411.12[M+H]⁺; C₂₇H₂₆N₂O₂,Mono-isotopic mass=410.20

¹H NMR (400 MHz, D₆-DMSO) δ 13.67 (s, 1H), 7.97 (d, J=9.3 Hz, 1H), 7.69(dd, J=9.3, 2.5 Hz, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.46 (m, 2H), 7.23 (m,1H), 7.15 (m, 2H), 6.93 (m, 2H), 6.76 (m, 2H), 3.97 (t, J=9.6 Hz, 2H),3.87 (t, J=7.4 Hz, 2H), 3.69 (s, 3H), 3.09 (t, J=9.6 Hz, 2H), 2.83 (t,J=7.4 Hz, 2H), 2.49 (s, 3H).

(al)4-methyl-8-phenoxy-1-(2-phenylpropyl)-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=8.72 min, m/z=395.11[M+H]⁺; C₂₇H₂₆N₂O, Mono-isotopicmass=394.20

¹H NMR (400 MHz, D₆-DMSO) δ 13.81 (s, 1H), 8.01 (d, J=9.3 Hz, 1H), 7.73(dd, J=9.3, 2.5 Hz, 1H), 7.51 (m, 2H), 7.44 (d, J=2.5 Hz, 1H), 7.28 (m,1H), 7.22 (m, 5H), 7.09 (m, 2H), 3.92 (m, 2H), 3.67 (dd, J=15.0, 9.4 Hz,1H), 3.38 (m, 1H), 3.04 (m, 2H), 2.88 (m, 1H), 2.46 (s, 3H), 1.04 (d,J=7.0 Hz, 3H).

(am)8-cyano-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-d]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.59 min, m/z=314.12[M+H]⁺; C₂₁H₁₉N₃, Mono-isotopicmass=313.16

¹H NMR (400 MHz, D₆-DMSO) δ 14.21 (s, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.11(dd, J=8.9, 1.6 Hz, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.34 (m, 2H), 7.26 (m,2H), 7.17 (m, 1H), 4.25 (t, J=7.1 Hz, 2H), 4.10 (t, J=9.6 Hz, 2H), 3.12(m, 4H), 2.50 (s, 3H).

(an)8-hydroxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 2 and Purification Method 1. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=6.75 min, m/z=305.11[M+H]⁺; C₂₀H₂₀N₂O, Mono-isotopicmass=304.16

¹H NMR (400 MHz, D₆-DMSO) δ 13.51 (s, 1H), 10.44 (s, 1H), 7.82 (d, J=9.2Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.44 (dd, J=9.2, 2.3 Hz, 1H), 7.33 (m,4H), 7.24 (m, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.90 (t, J=9.6 Hz, 2H), 3.08(t, J=7.4 Hz, 2H), 3.04 (t, J=9.6 Hz, 2H), 2.45 (s, 3H).

(ao) 8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride;

Prepared using General Method 3 and Purification Method 4. The productwas then converted to the hydrochloride salt by the addition of 1 Nhydrochloric acid, followed by evaporation.

LCMS (method B): Rt=8.52 min, m/z=367.08[M+H]⁺; C₂₅H₂₂N₂O, Mono-isotopicmass=366.17

¹H NMR (400 MHz, D₆-DMSO) δ 13.79 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=9.3Hz, 1H), 7.72 (dd, J=9.3, 2.5 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.46 (m,2H), 7.19 (m, 6H), 7.03 (m, 2H), 3.99 (t, J=9.5 Hz, 2H), 3.94 (t, J=7.6Hz, 2H), 3.16 (t, J=9.5 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H).

Example 56,8-Dimethoxy-1-(4-hydroxyphenyl)-4-methylpyrrolo[3,2-c]quinolinetrifluoroacetate

A mixture of6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(0.1 g; see Example 3(i) above), palladium on carbon (10%, 0.1 g) anddiphenyl ether (5 mL) was heated at 200° C. for 2 hours. The mixture wascooled to room temperature, diluted with methanol and filtered throughCelite™. The filtrate was evaporated to dryness and the residue waspurified using Purification Method 1 to give the title compound (0.004g).

LCMS (Method B): Rt=6.50 min, m/z=335.13 [M+H]⁺; C₂₀H₁₈N₂O₃,Mono-isotopic mass=334.13

¹H-NMR (400 MHz, D₆-DMSO): δ 10.24 (s, br, 1H), 7.92 (d, J=3.3 Hz, 1H),7.45 (m, 2H), 7.44 (d, J=3.3 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.06 (m,2H), 6.25 (d, J=2.4 Hz, 1H), 4.13 (s, 3H), 3.52 (s, 3H), 3.15 (s, 3H).

Example 68-Methoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride (i)1-(4-Bromo-3-fluorophenyl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

The sub-title compound was prepared from the appropriate intermediatesby analogy with General Method 3 (above) and was purified usingPurification Method 1.

¹H NMR (400 Mz, D₄-methanol) δ 7.86 (t, J=8.1 Hz, 1H), 7.77 (d, J=9.3Hz, 1H), 7.51 (dd, J=9.2, 2.4 Hz, 1H), 7.47 (dd, J=9.3, 2.7 Hz, 1H),7.31 (m, 1H), 6.42 (d, J=2.7 Hz, 1H), 4.45 (t, J=9.3 Hz, 2H), 3.47 (s,3H), 3.42 (t, J=9.3 Hz, 2H), 2.64 (s, 3H).

The compound was converted to the free base by partitioning betweendichloromethane and aqueous sodium bicarbonate solution, followed byevaporation of the organic phase. The free base was used directlywithout further purification.

(ii)8-Methoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride

A mixture of1-(4-bromo-3-fluorophenyl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(0.075 g; see step (i) above), 1-methylpiperazine (0.023 g), palladiumacetate (0.003 g), 2-(di-tert-butylphosphino)biphenyl (0.003 g), sodiumtert-butoxide (0.026 g) and toluene (5 mL) was stirred and heated at 80°C. under an atmosphere of nitrogen overnight. The mixture was thenstirred and heated at reflux overnight. Further palladium acetate (0.003g) and 2-(di-tert-butylphosphino)biphenyl (0.003 g) was added and themixture was stirred and heated at reflux overnight. The mixture wasevaporated to dryness and the residue was partitioned between ethylacetate and aqueous sodium bicarbonate solution. The organic layer waswashed with water, aqueous brine solution, dried (MgSO₄) and filtered.The filtrate was evaporated to dryness and the residue was purifiedusing Purification Method 1. The product was then converted to thehydrochloride salt by the addition of 1 N hydrochloric acid, followed byevaporation to give the title compound (0.009 g).

LCMS (Method B): Rt=4.79 min, m/z=407.17 [M+H]⁺; C₂₄H₂₇FN₄O,Mono-isotopic mass=406.22

¹H-NMR (400 MHz, D₄-methanol): δ 7.75 (d, J=9.2 Hz, 1H), 7.45 (dd,J=9.2, 2.7 Hz, 1H), 7.42 (dd, J=12.9, 2.3 Hz, 1H), 7.37 (dd, J=8.4, 2.3Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 6.45 (d, J=2.7 Hz, 1H), 4.40 (t, J=9.5Hz, 2H), 3.68 (s, br, 4H), 3.45 (s, 3H), 3.40 (t, J=9.5 Hz, 2H), 3.40,3.25 (broad singlets, 4H), 3.00 (s, 3H), 2.62 (s, 3H).

Example 74-Methyl-8-phenylamino-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate (i)8-Bromo-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

The sub-title compound was prepared from the appropriate intermediatesby analogy with General Method 3 (above) and then used withoutpurification.

LCMS (method A): Rt=2.42 min, m/z=367 [M+H]⁺; C₂₀H₁₉BrN₂, Mono-isotopicmass=367.07

(ii)4-Methyl-8-phenylamino-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolineformate

A mixture of8-bromo-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline(0.308 g; see step (i) above), aniline (0.064 mL)2-dicyclohexyl-phosphino 2′-dimethylamino biphenyl (0.028 g),tris-(dibenzylidieneacetone)-dipalladium (0.032 g), sodium tert-butoxide(0.094 g) and toluene (8 mL) was degassed and then heated in themicrowave at 140° C. for 30 minutes. The mixture was diluted with water,extracted with ethyl acetate, washed with water, dried (MgSO₄) andfiltered. The filtrate was evaporated to dryness and the residue waspurified using Purification Method 1 to give the title compound (0.08g).

LCMS (method B): Rt=8.61 min, m/z=380.12[M+H]⁺; C₂₆H₂₅N₃, Mono-isotopicmass=379.20

¹H NMR (400 MHz, D₆-DMSO) δ 8.40 (s, 1H), 8.27 (s, 1H), 7.70 (d, J=9.2Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.35 (dd, J=9.2, 2.4 Hz, 1H), 7.23 (m,2H), 7.17 (m, 5H), 7.06 (m, 2H), 6.87 (m, 1H), 3.73 (m, 4H), 3.00 (t,J=9.4 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.38 (s, 3H).

Example 8[4-Methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[2,3-c]quinoline-8-oyl]piperidinehydrochloride (i)4-Methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylicacid

Crude methyl4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylate(see Example 4 (t) above) was dissolved in a mixture of methanol (3 mL)and water (3 mL) and sodium hydroxide (0.2 g) was added and the mixturewas stirred at room temperature for 1 hour. The mixture was evaporatedto dryness and the residue was dissolved in ethyl acetate and washedwith aqueous citric acid solution, dried (MgSO₄) and filtered. Thefiltrate was evaporated to dryness and the residue was purified usingPurification Method 1. The product (sub-title compound) was useddirectly without further purification.

(ii)[4-Methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[2,3-c]quinoline-8-oyl]piperidinehydrochloride

A mixture of crude4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylicacid (0.05 g; see step (i) above), piperidine (0.085 g), ethyl acetate(2 mL), pyridine (0.2 mL) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.051 g) was stirred at room temperature for 2hours. The resultant mixture was evaporated to dryness and the residuewas purified by Purification Method 1. The product was then converted tothe hydrochloride salt by the addition of 1 N hydrochloric acid,followed by evaporation to give the title compound (0.023 g).

LCMS (method B): Rt=7.06 min, m/z=400.14[M+H]⁺; C₂₆H₂₉N₃O, Mono-isotopicmass=399.23

¹H NMR (400 MHz, D₆-DMSO) δ 13.88 (s, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.99(d, J=8.8 Hz, 1H), 7.85 (dd, J=8.8, 1.5 Hz, 1H), 7.32 (m, 4H), 7.23 (m,1H), 4.13 (t, J=7.7 Hz, 2H), 4.07 (t, J=9.5 Hz, 2H), 3.59 (br, 2H), 3.31(br, 2H), 3.12 (m, 4H), 2.51 (s, 3H), 1.50 (br m, 6H).

Example 94-Methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolinehydrochloride Large Scale Process Outline.

Step No. Operation Charges 1 Set-up 10 L flange flask and purge with N₂.2 Charge to flask stage 4-chloro-3-(2-chloroethyl)- 745.3 g2-methyl-6-phenoxyquinoline (1 eq.; see Preparation 4 above). 3 Chargeto flask ethylene glycol (5 volumes). 3700 mL 4 Nitrogen was bubbledthrough the reaction mixture for 30 min. 5 Phenethylamine (2.0 eq) wasadded and the flask 560 mL evacuated and purged with N₂ 3x. 6 Thereaction mixture was heated to 180° C. under an atmosphere of N₂. 7 Thereaction was analysed for completion after 2 h by LC analysis and everyhour thereafter until reaction complete. The reaction was deemedcomplete when the level of reaction intermediate at rt 16.8 min <1% . 8The reaction mixture was allowed to cool to room temperature and left tostir overnight. 9 Water (5 volumes) was added to the reaction 3700 mLmixture. 10 The reaction mixture was acidified to pH 1 using ~10 mLconc. HCl. 11 The mixture was extracted using DCM (2 × 5 2 × 3700 mLvolumes). 12 The DCM extracts were combined and washed 3700 mL withwater (5 volumes). 13 The DCM extracts were dried over MgSO₄. 14 The DCMmixture was distilled under atmospheric pressure until precipitatestarts to form. 15 Acetone (6 volumes) was added and the 4500 mLremaining amount of DCM removed by distillation until a constant headtemperature was reached. Add further amount of acetone to increasemobility of slurry if required. 16 The mixture was allowed to cool toroom temperature and stirred for 1 h. 17 The precipitate was filteredand the solid cake 1500 mL washed with acetone (2 volumes). 18 The crudestage 3 was dissolved in EtOH 3000 mL (4 volumes) at reflux. 19 Themixture was allowed to cool to 70° C. and a polish and filter carriedout transferring to mixture to a 10 L flange flask. 20 The filteredmixture was allowed to cool to room 1500 mL temperature resulting in theformation of a precipitate. The precipitate was filtered and the wetcake washed with acetone (2 volumes). A further recrystallisation can beused to improve purity. 21 The title compound was dried in a vacuum ovento constant weight at 50° C.

Example 10

Compounds of Examples 1 to 8 above may be formulated for topicaladministration according to any of the following formulations (wherein“active compound” represents any of the compounds of Examples 1 to 8above).

Excipient Formulation (w/w) A(i) A(ii) B(i) B(ii) C(i) C(ii) D E Benzylalcohol 1.0 1.0 1.0 1.0 — — 2.0 2.1 Potassium — — — — 0.04 0.1 — —sorbate EDTA — — — — 0.04 0.1 — — Ethanol 9.9 10 7.7 7.7 — — 10.2 10Propylene 15.2 15 5.7 5.7 — — 15.0 14.9 glycol Glycerol — — 25.1 25 — —— 10.2 Kleptose ™ — — — 20.1 20 — — Klucel ™ — — — 2.0 2.0 — — HEC 2 22.2 2.0 — — 2 2.0 Water — — — — 75.82 75.8 68.8 58.8 Citrate/ 69.8 7056.3 56.6 — — — — phosphate pH 5.5 buffer Active 2.0 2.0 2.0 2.0 2.0 2.02.0 2.0 compound

Alternative formulations include those based upon B(i) and B(ii) above,but having increased propylene glycol concentration (but less than 15%w/w) and decreased glycerol concentration.

Example 11

Compounds of Examples 1 to 8 above were found to possess activity inbiological tests described above. Biological activity that wasdetermined included a log kill, at 25, 10 or 5 μg/mL of test compound,of above 0.5 (e.g. from 0.5 to 7) against stationary phase and/orpersister bacteria of the types E. coli, Enterococcus, Staph. aureus,Streptococcus and Mycobacterium tuberculosis.

Indeed, the following compounds had the activity indicated.

-   (a) The compound of Example 1(a), when tested against Staph. aureus    stationary phase bacteria at 5 μg/mL of test compound, displayed a    log kill of 3.55.-   (c) The compound of Example 1(h), when tested against E. coli    persister bacteria at 25 μg/mL of test compound, displayed a log    kill of 3.83.

Abbreviations

-   br=broad (in relation to NMR)-   d=doublet (in relation to NMR)-   DCM=dichloromethane-   DMSO=dimethylsulfoxide-   EDTA=ethylenediaminetetraacetic acid-   HEC=hydroxyethylcellulose-   HPLC=high performance liquid chromatography-   LC=liquid chromatography-   m=multiplet (in relation to NMR)-   MBC=minimum bactericidal concentration-   Me=methyl-   min.=minute(s)-   MIC=minimum inhibitory concentration-   MS=mass spectroscopy-   NMR=nuclear magnetic resonance-   q=quartet (in relation to NMR)-   s=singlet (in relation to NMR)-   t=triplet (in relation to NMR)

Prefixes n-, s-, i-, t- and tent- have their usual meanings normal,secondary, iso, and tertiary.

1-49. (canceled)
 50. A compound of formula (Ia), or apharmaceutically-acceptable salt thereof, wherein the compound offormula (Ia) is represented by the structure:

wherein, R¹ represents C₁₋₅ alkyl which is optionally substituted byC₃₋₅ cycloalkyl, phenoxy, benzodioxanyl, benzodioxolyl or phenyl, whichphenyl group is optionally substituted by one or more substituentsselected from halo, methyl and methoxy; C₃₋₆ cycloalkyl, which isoptionally fused to a benzene ring to provide a benzo-fused cycloalkylgroup; phenyl, which phenyl group is optionally substituted by one ormore substituents selected from halo, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, whichalkoxy group is optionally substituted by N(CH₃)₂, phenoxy, whichphenoxy group is optionally substituted by one or more substituentsselected from methoxy, halo, pyridyloxy and piperazinyl, whichpiperazinyl group is optionally substituted by methyl; pyridyl which isoptionally substituted by methoxy or phenoxy; or piperidinyl which isoptionally substituted by C₁₋₂ alkyl, which alkyl group is optionallysubstituted by phenyl; R² represents unsubstituted C₁₋₃ alkyl; R^(3a)and R^(3c) independently represent H, C₁₋₄ alkoxy optionally substitutedby one or more halo atoms, or phenoxy optionally substituted by one ormore substituents selected from halo, methyl and methoxy; provided thatR^(3a) and R^(3c) do not both represent H; and R^(ab) and R^(3″) bothrepresent H.
 51. A method of killing clinically latent microorganisms ina mammal comprising administering a compound of formula I, as defined inclaim 50, to a mammal in need thereof.
 52. A method of treating orpreventing a microbial infection in a mammal, comprising administeringto a mammal in need thereof an effective amount of the compound offormula I, as defined in claim
 50. 53. A method of sterilizing anobject, comprising applying to said object to be sterilized an effectiveamount of the compound of formula I, as defined in claim
 50. 54. Amethod of preserving an inorganic or organic material, comprisingcontacting, combining or mixing said inorganic or organic material withan effective amount of the compound of formula I, as defined in claim50.
 55. A combination product comprising (A) compound of formula I, asdefined in claim 50 and (B) an antimicrobial agent, wherein each of thecomponents (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.
 56. Thecombination product according to claim 55, wherein the antimicrobialagent is a penicillin (optionally combined with a β-lactamaseinhibitor), a cephalosporin, a monobactam, a carbapenem (optionallycombined with a renal enzyme inhibitor), a 1-oxa-β-lactam, atetracycline, an aminoglycoside, a macrolide, a ketolide, a lincosamine,clindamycin, clindamycin 2-phosphate, a phenicol, a steroid, aglycopeptide, an oxazolidinone, one or more streptogramins, a polymyxin,a lysostaphin, an actinomycin, actinonin, 7-aminoactinomycin D,antimycin A, antipain, bacitracin, cyclosporin A, echinomycin, agramicidin, myxothiazol, nisin, paracelsin, valinomycin, viomycin, alipopeptide, a sulfonamide (optionally in combination withtrimethoprim), trimethoprim, isoniazid, rifampicin, rifabutin,pyrazinamide, ethambutol, streptomycin, dapsone, clofazimine, anitroimidazole, a nitrofuran, a quinolone, azaserine, bestatin,D-cycloserine, 1,10-phenanthroline, 6-diazo-5-oxo-L-norleucine,L-alanyl-L-1-aminoethyl-phosphonic acid, an aureolic acid, abenzochinoide a coumarin-glycoside, irgasan, anepipolythiodixopiperazine, cerulenin a glucosamine, staurosporine, amacrolactam, a taxoid, a statin, a polyphenolic acid, lasalocid A,lonomycin A, monensin, nigericin, salinomycin, fusaric acid,blasticidine S, nikkomycin, nourseothricin, puromycin, adenine9-β-D-arabinofuranoside, 5-azacytidine, cordycepin, formycin A,tubercidin, tunicamycin, methenamine (hexamine), piericidin A,stigmatellin, actidione, anisomycin, apramycin, coumermycin A1,L(+)-lactic acid, a cytochalasin, emetine, ionomycin, an azoleantifungal, a polyene antifungal, griseofulvin, caspofungin,flucytosine, a combination of caspofungin and flucytosine, or anallylamine antifungal.
 57. The combination product according to claim56, wherein the antimicrobial agent is co-amoxiclav.
 58. The combinationproduct according to claim 56, wherein the antimicrobial agent isazithromycin.
 59. The combination product according to claim 56, whereinthe antimicrobial agent is telithromycin.
 60. The combination productaccording to claim 56, wherein the antimicrobial agent is linezolid. 61.The combination product according to claim 56, wherein the antimicrobialagent is daptomycin.
 62. The combination product according to claim 56,wherein the antimicrobial agent is levofloxacin.
 63. The combinationproduct according to claim 56, wherein the antimicrobial agent ismoxifloxacin.
 64. The combination product according to claim 55, whichproduct is a pharmaceutical formulation including a compound of formulaI, as defined in claim 50 and an antimicrobial agent, as defined inclaim 56, or a pharmaceutically-acceptable derivative thereof, inadmixture with a pharmaceutically-acceptable adjuvant, diluent orcarrier.
 65. The combination product according to claim 55, whichproduct is a kit of parts comprising components: (I) a pharmaceuticalformulation including a compound of formula I, as defined in claim 50,in admixture with a pharmaceutically-acceptable adjuvant, diluent orcarrier; and (II) a pharmaceutical formulation comprising anantimicrobial agent, as defined in claim 56, or apharmaceutically-acceptable derivative thereof, in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier, whichcomponents (I) and (II) are each provided in a form that is suitable foradministration in conjunction with the other.
 66. A formulationcomprising the compound of formula I, as defined in claim 50 and asterilizing agent, or a salt and/or solvate thereof.
 67. A method ofkilling clinically latent microorganisms in a mammal, the methodcomprising administering to said mammal in need of having clinicallylatent microorganisms killed an effective amount of the combinationproduct according to claim
 55. 68. A method of treating or preventing amicrobial infection in a mammal, the method comprising administering tosaid mammal in need thereof an effective amount of the combinationproduct according to claim
 55. 69. A pharmaceutical formulationcomprising the compound of formula I, as defined in claim 50, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.
 70. A method of treating a mammal afflicted with a diseasecomprising administering to said afflicted mammal an effective amount ofthe compound of formula I, as defined in claim 50, wherein said diseaseis tuberculosis, anthrax, abscesses, acne vulgaris, actinomycosis,bacilliary dysentry, bacterial conjunctivitis, bacterial keratitis,botulism, Buruli ulcer, bone and joint infections, bronchitis (acute orchronic), brucellosis, burn wounds, cat scratch fever, cellulitis,chancroid, cholangitis, cholecystitis, cutaneous diphtheria, cysticfibrosis, cystitis, diffuse panbronchiolitis, diphtheria, dental caries,diseases of the upper respiratory tract, empymea, endocarditis,endometritis, enteric fever, enteritis, epididymitis, epiglottitis,erysipelas, erysipeloid, erythrasma, eye infections, furuncles,Gardnerella vaginitis, gastrointestinal infections, genital infections,gingivitis, gonorrhoea, granuloma inguinale, Haverhill fever, infectedburns, infections following dental operations, infections in the oralregion, infections associated with prostheses, intraabdominal abscesses,Legionnaire's disease, leprosy, leptospirosis, listeriosis, liverabscesses, Lyme disease, lymphogranuloma venerium, mastitis,mastoiditis, meningitis and infections of the nervous system, mycetoma,nocardiosis, non-specific urethritis, opthalmia, osteomyelitis, otitis,orchitis, pancreatitis, paronychia, pelveoperitonitis, peritonitis,peritonitis with appendicitis, pharyngitis, phlegmons, pinta, plague,pleural effusion, pneumonia, postoperative wound infections,postoperative gas gangrene, prostatitis, pseudo-membranous colitis,psittacosis, pulmonary emphysema, pyelonephritis, pyoderma, Q fever,rat-bite fever, reticulosis, Ritter's disease, salmonellosis,salpingitis, septic arthritis, septic infections, septicameia,sinusitis, skin infections, syphilis, systemic infections, tonsillitis,toxic shock syndrome, trachoma, tularaemia, typhoid, typhus, urethritis,wound infections, yaws, aspergillosis, candidiasis, cryptococcosis,favus, histoplasmosis, intertrigo, mucormycosis, tinea, onychomycosis,pityriasis versicolor, ringworm, sporotrichosis, or infections withMSSA, MRSA, Staph. epidermidis, Strept. agalactiae, Strept. pyogenes,Escherichia coli, Klebs. pneumoniae, Klebs. oxytoca, Pr. mirabilis, Pr.rettgeri, Pr. vulgaris, Haemophilis influenzae, Enterococcus faecalis orEnterococcus faecium.
 71. A method of reducing the dose of anantimicrobial agent required to treat a microbial infection, comprisingco-administering the antimicrobial agent with the compound of formula I,as defined in claim 50, to a patient with a microbial infection, whereinthe dose of the microbial agent required to treat the patient is lowerin the presence than in the absence of said compound of formula I.
 72. Amethod of treating or preventing a microbial infection as claimed inclaim 68, wherein the amount of antimicrobial agent required to treatthe microbial infection is reduced compared to that required in theabsence of a compound of formula I.
 73. A method of treating a protozoaldisease in a mammal, the method comprising administering to said mammalafflicted with a protozoal disease an effective amount of the compoundof formula I as defined in claim
 50. 74. The method of treating aprotozoal disease in a mammal according to claim 73, wherein theprotozoal disease is not malaria or amoebiasis.
 75. The combinationproduct as claimed in claim 55, further comprising a carrier for topicaladministration.
 76. The pharmaceutical formulation as claimed in claim69, further comprising a carrier for topical administration.
 77. Aprocess for the preparation of the compound of formula I as defined inclaim 50, which comprises: (a) reacting a compound of formula II,

wherein L¹ and L² independently represent a leaving group and R², R^(3a)and R^(ao) are as defined in claim 50, with a compound of formula III,R¹—NH₂  III wherein R¹ is as defined in claim 50; or (b) deprotecting aprotected derivative of the compound of formula I.
 78. A compoundaccording to claim 50, wherein R¹ represents 3-methylbut-1-yl,1-methylbenzimidazol-2-yl, cyclopropyl, cyclopropylmethyl,2-phenoxyethyl, benzodioxol-5-ylmethyl, 6-methoxypyridin-3-yl,6-phenoxypyridin-3-yl, 3-hydroxyphenyl, 3-hydroxy-5-methylphenyl,4-hydroxyphenyl, 4-(2-dimethylaminoethoxy)phenyl,3-fluoro-4-(4-methylpiperazin-1-yl)phenyl, 4-(pyridin-3-yloxy)phenyl,benzodioxan-2-ylmethyl, 1-benzylpiperidin-4-yl, cyclohexyl,1,2,3,4-tetrahydronaphth-1-yl, 1-phenylethyl, 2-phenylethyl, phenyl,4-iso-propylphenyl, 4-methoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl,benzyl, (2-methylphenyl)methyl, indan-1-yl or indan-2-yl.
 79. A compoundaccording to claim 50, wherein R¹ represents 3-methoxypropyl,ethoxycarbonylmethyl, 2-(methoxycarbonyl)ethyl, 2-(ethoxycarbonyl)ethyl,3-(methoxycarbonyl)propyl, 3-(ethoxycarbonyl)propyl,1-benzylpyrrolidin-3-yl, 1-methylpiperidin-4-yl,tetrahydrofuran-2-ylmethyl, 2-pyridylmethyl, 5-methylpyrazin-2-ylmethyl,2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 3-(1-pyrrolidin-2-onyl)propyl,2-methylphenyl, 4-(piperidin-1-yl)phenyl, 4-(3-pyridyl)phenyl,2-phenylpropyl, (S)-indan-1-yl, (R)-indan-1-yl, 2-(4-chlorophenyl)ethyl,2-(4-methoxyphenyl)ethyl or 4-(4-fluorophenoxy)phenyl.
 80. A compoundaccording to claim 50, wherein R² represents methyl.
 81. A compoundaccording to claim 50, wherein R^(3a) represents H.
 82. A compoundaccording to claim 50, wherein R^(3c) represents C₁₋₄ alkoxy or phenoxy.83. A compound according to claim 50, selected from the group consistingof:6,8-dimethoxy-4-methyl-1-(3-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;6,8-dimethoxy-4-methyl-1-(2-phenoxyethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;1-cyclopropyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;8-methoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;{2-[4-(8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-1-yl)-phenyoxy]ethyl}dimethylamine;8-methoxy-4-methyl-1-[4-(pyridin-3-yloxy)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-8-phenoxy-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-benzyl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline1-(indan-2-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline4-methyl-6-phenoxy-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-benzyl-4-methyl-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-(indan-2-yl)-4-methyl-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;8-methoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinolin-6-ol;1-(1-benzyl-piperidin-4-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-(indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-(benzodioxan-2-ylmethyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-8-phenoxy-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-cyclohexyl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;8-ethoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;1-(4-methoxyphenyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;4-methyl-1-(2-methylphenyl)methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-8-phenoxy-1-(4-iso-propylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;4-methyl-8-phenoxy-1-(1-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;8-methoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;(27)6,8-dimethoxy-1-(4-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-1-(3-hydroxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-1-(3-hydroxy-5-methylphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;8-methoxy-1-(4-methoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;8-trifluoromethoxy-1-(4-phenoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-4-methyl-1-[4-(pyridin-3-yloxy)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-benzyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-4-methyl-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-1-(2-phenylethyl)-8-trifluoromethoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-1-(indan-1-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;6,8-dimethoxy-4-methyl-1-[(6-phenoxy)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-1-[(6-methoxy)pyridin-3-yl]-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-(benzodioxol-5-ylmethyl)-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;6,8-dimethoxy-4-methyl-1-(3-methylbutyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;1-cyclopropylmethyl-6,8-dimethoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;8-methoxy-4-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-{4-[2-(N,N-dimethylamino)ethoxy]phenyl}-4-methyl-8-phenoxy-2,3-dihydro-1,4-pyrrolo[3,2-c]quinoline;1-[4-(4-fluorophenoxy)phenyl]-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-(benzodioxan-2-ylmethyl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-cyclohexyl-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;8-methoxy-4-methyl-1-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-8-phenoxy-1-[4-(3-pyridyl)phenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;4-methyl-8-phenoxy-1-[2-(3-pyridyl)ethyl]-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;4-methyl-8-phenoxy-1-(2-pyridylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;4-methyl-1-(5-methylpyrazin-2-ylmethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-[3-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-1-yl)propyl]-pyrrolidin-2-one;4-methyl-8-phenoxy-1-[2-(2-pyridyl)ethyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;ethyl3-(8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)propionate;ethyl4-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)butanoate;methyl4-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)butanoate;ethyl(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)acetate;4-methyl-1-(1-methylpiperidin-4-yl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-(1-benzylpyrrolidin-3-yl)-8-methoxy-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;methyl3-(4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)propionate;1-((S)-indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;1-((R)-indan-1-yl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;1-(3-methoxypropyl)-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;4-methyl-8-phenoxy-1-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-[2-(4-chlorophenyl)ethyl]-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;1-[2-(4-methoxyphenyl)ethyl]-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-8-phenoxy-1-(2-phenylpropyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;8-methoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline;4-methyl-8-phenylamino-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline;or a pharmaceutically-acceptable salt thereof
 84. A compound accordingto claim 83, which is8-methoxy-4-methyl-1-(4-phenoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline,or a pharmaceutically-acceptable salt thereof.
 85. A compound accordingto claim 83, which is1-indan-2-yl-4-methyl-8-phenoxy-2,3-dihydro-1H-pyrrolo-[3,2-c]quinoline,or a pharmaceutically-acceptable salt thereof.
 86. A compound accordingto claim 83, which is4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline,having the structure:

or a pharmaceutically-acceptable salt thereof.
 87. A compound accordingto claim 86, which is4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinolinehydrochloride.